Substituted diamino heterocyclic carboxamide compound and a composition containing the compound and use thereof

ABSTRACT

A substituted amino heterocyclic carboxamide compound as represent by formula (Φ), or a pharmaceutically acceptable salt, a prodrug, a hydrate or a solvent compound, a crystal form, a stereoisomer or an isotopic variant of the compound, and a pharmaceutical composition thereof, and the use thereof as an FLT3/AXL kinase inhibitor for treating acute myelocytic leukemia.

FIELD OF THE INVENTION

The present disclosure relates to the field of pharmaceuticaltechnology, particularly relates to a substituted diamino heterocycliccarboxamide compound, a composition comprising the same and use thereof.More specifically, the present disclosure relates to some deuterated6-ethyl-3-((3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamides.These deuterated compounds are demonstrated as inhibitors of AXL andFLT3 protein tyrosine kinase, which can be used in the treatment ofdiseases mediated by AXL and/or FLT3, and have better pharmacokineticand pharmacodynamic properties.

BACKGROUND OF THE INVENTION

Acute Myeloid Leukemia (Acute Myelocytic Leukemia, AML) is a diseasecaused by the malignant proliferation of hematopoietic progenitor cellsof bone marrow. The poorly differentiated progenitor cells lose theirnormal functions which disrupts the normal hematopoietic process,leading to infections, bleeding and multiple organ dysfunctions. Theoverall incidence of AML is 3.4/100,000, and the median of patients' ageis 67. The onset of disease occurs before the age of 65 for more thanhalf of the patients. The prognosis of AML patients is generally poor,especially for the elderly patients and those with poor physicalcondition.

FMS-like tyrosine kinase 3 (FLT3) is a type Ill receptor tyrosinekinase, which plays a key role in the proliferation, differentiation andapoptosis of hematopoietic cells and lymphocytes. The abnormalactivation of FLT3 is closely related to the occurrence and developmentof AML. Studies have shown that more than one-third of the AML patientsare accompanied by abnormal activation of FLT3.

The structure of FLT3 includes an extracellular domain, a transmembranedomain, and an intracellular tyrosine kinase domain that are composed of5 immunoglobulin-like structures. FLT3 is mainly expressed on the cellsurface of normal hematopoietic hepatocytes and hematopoietic progenitorcells, and its ligands are mainly expressed in the bone marrow stromalcells. When the ligand is bound to the extracellular domain of FLT3, thedimerization of FLT3 receptors and the autophospholation of theintracellular tyrosine kinase domain are promoted at the same time,activating a series of downstream signaling pathways, such as Ras/MAPK,PI3K/Akt/mTOR and STAT5, thereby regulating cell proliferation anddifferentiation. FLT3 mutations usually lead to its abnormal activation,and the autophosphorylation in the absence of binding with ligand, whichactivate the downstream signaling pathways, leading to the abnormalproliferation of hematopoietic cells and lymphocytes and triggeringvarious malignant blood diseases.

There are two main types of FLT3 activation mutations, including theinternal tandem duplication (ITD) mutations in the near-membrane domainand the point mutations of the activation loop in the tyrosine kinasedomain (TXD).

The ITD mutation refers to an insertion of repeated tandem amino acidsequence in the near-membrane domain of FLT3. About 17% to 34% of AMLpatients are accompanied by this mutation, which is also detected in themyelodysplastic syndrome (MDS). Normally, the near-membrane domain has aself inhibitory function on FLT3, which can inhibit the phosphorylationof the kinase domain. However, the ITD mutation may destroy theself-inhibitory activity of the near-membrane domain, resulting in theloss of the self-inhibition, and FLT3 is therefore, in a continuouslyactivated. conformation. AML patients with the ITD mutation are oftenaccompanied by the clinical features such as an increase in the numberof leukocytes and an increase in the percentage of primitive bone marrowcells and blood cells. Due to the high rate of AML recurrence and manyadverse reactions after the ITD mutation, the adverse prognosis ofpatients with ITD mutation is worse than that of ordinary AML patients.

The point mutations of FLT3 mainly occur in the activation loop of TKD.Insertion or deletion of exon 20 of FLT3 gene can make the 835 asparticacid residue mutate at the C-terminal of TKD in FLT3. and about 7% ofAML patients have this mutation. The most common mutation is Asp835Tyr,and other mutations such as Asp835Val, Asp835Glu and Asp835Asn are alsofound. These point mutations can stabilize the activation in theconformation of ATP binding, thereby enabling the continuous activationof FLT3.

Given that FLT3 plays a key role in the pathogenesis of AMLFLT3-targeted therapy has become the focus of anti-AML drug research.

AXL is a receptor-type tyrosine kinase, and is a protein having a celltransmembrane domain in the center, a tyrosine kinase domain on thecarboxy-terminal side, and an extracellular domain on the amino-terminal side. So far, the overexpression of AXL has been reported inacute leukemia, astrocytoma, breast cancer, colorectal cancer,esophageal cancer, gastrointestinal stromal tumor, gastric cancer,hepatocellular carcinoma, Kaposi's sarcoma, lung cancer; melanoma,ovarian cancer, osteosarcoma, pancreatic ductal adenocarcinoma, renalcell carcinoma, prostate cancer, thyroid cancer, and endometrial cancer.

In addition, various cancers have been reported, in which AXL andresistance to chemotherapy are related. In the AML clinical samples,cells that have acquired resistance to chemotherapy also show theoverexpression of AXL, and AML cell lines with stable expression of AXLalso show the chemotherapy resistance. Therefore, AXL is considered tobe the cause of drug resistance.

Gilteritinib (its chemical name is6-ethyl-3-((3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamidewith the following structural formula) is a FLT3 inhibitor developed byAstellas Pharma Inc. of Japan, which can effectively inhibit ITD andTKD, and is used in the treatment of adult patients with relapsed orrefractory AML who are positive for FLT3 mutations. It can also inhibitkinases such as AXL. Clinical trials have shown that Gilteritinib caneffectively inhibit the mutation and activity of FLT3, and cansignificantly prolong the life of patients at the same time. In July2017, FDA granted it the orphan drug designation; in October 2017, FDAgranted it the fast-track certification; and in November 2018, FDAapproved it for marketing.

Poor absorption, distribution, metabolism, and/or excretion (ADME)properties are known to be the primary causes of clinical trial failureof many drug candidates. At present, many marketed drugs havelimitations on their application due to their poor ADME properties. Therapid metabolism of many drugs, which could have been effective intreating diseases, could make them difficult to be used as drugs due totheir rapid removal from the body. Although a frequent or high-doseadministration may solve the problem of rapid drug clearance, thisapproach will bring problems such as poor compliance of patients, sideeffects caused by high-dose administration and increased treatmentcosts. In addition, drugs that are rapidly metabolized may also exposethe patients to undesirable toxic or reactive metabolites.

Although Gilteritinib can treat AML effectively, there are serious unmetclinical needs in the treatment of AML patients with positive FLT3mutations, and discovering novel compounds that can treat AML with goodoral bioavailability and drugability is still a challenging task.Therefore, it is still necessary to develop compounds with selectiveinhibitory activity or better pharmacodynamic/pharmacokinetic propertiesas therapeutic agents for the FLT3 kinase-mediated diseases in thisfield. The present disclosure provides such compounds.

SUMMARY OF THE INVENTION

In view of the above technical problems, the present disclosure providesa new deuterated amino heterocyclic carboxamide compound, a compositioncomprising the same and use thereof. The compounds have betterinhibitory activity against FLT3 and AXL, kinases, lower side effects,higher selectivity, and better pharmacodynamic/pharmacokineticproperties, and can be used in treating cancers related to AML andothers.

As used herein, the term “compound of the present disclosure” (or“compound disclosed herein”) refers to the compounds represented byformula (Φ), (I) and (II). The term also includes pharmaceuticallyacceptable salts, prodrugs, hydrates, solvates, polymorphs,stereoisomers or isotopic variants of the compounds of formulae (Φ), (I)and (II).

In this regard, the technical solution adopted by the present disclosureis as follows:

In the first aspect, the present disclosure provides a compound offormula (Φ):

wherein,

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³ and R²⁴ are independently selectedfrom hydrogen or deuterium:

X¹ and X² are independently selected front CH₃, CD₃, CHD₂ or CH₂D;

X³ is selected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃, CHDCH₂D,CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ or CD₂CD₃;

Y¹, Y² and Y³ are independently selected from hydrogen or deuterium;

with the proviso that the compound described above contains at least onedeuterium atom;

or a pharmaceutically acceptable salt, prodrug, hydrate, solvate,polymorph, stereoisomer or isotopic variant thereof.

In another aspect, the present disclosure provides a pharmaceuticalcomposition. which comprises the compound of the present disclosure andpharmaceutically acceptable excipient(s). In a specific embodiment, thecompound of the present disclosure is provided in an effective amount inthe pharmaceutical composition. In a specific embodiment, the compoundof the present disclosure is provided in a therapeutically effectiveamount. In a specific embodiment, the compound of the present disclosureis provided in a prophylactically effective amount.

In another aspect, the present disclosure provides a method of preparingthe pharmaceutical composition described above, comprising the steps of:mixing the pharmaceutically acceptable excipient(s) with the compound ofthe present disclosure, thereby forming the pharmaceutical composition.

In another aspect, the present disclosure also provides a method oftreating the FLT3 kinase-mediated disease in a subject. The methodcomprises administering to the subject a therapeutically effectiveamount of the compound disclosed herein In a specific embodiment, thedisease such as cancer is mediated by FLT3. In a specific embodiment,the patient is diagnosed or identified as having an FLT3-related cancer.In a specific embodiment, the FLT3-mediated disease is AML. In aspecific embodiment, the compound is administered orally,subcutaneously, intravenously or intramuscularly. In a specificembodiment, the compound is administered chronically.

In another aspect, the present disclosure also provides a use of thecompound disclosed herein in the preparation of a medicament for thetreatment of diseases mediated by FLT3 kinase The use includesadministering to the subject a therapeutically effective amount of thecomp and disclosed herein In a specific embodiment, the disease ismediated by FLT3. In a specific embodiment, the patient is diagnosed oridentified as having an FLT3-related cancer. In a specific embodiment,the FLT3-mediated disease is AML. In a specific embodiment, the compoundis administered orally, subcutaneously, intravenously orintramuscularly. In a specific embodiment, the compound is administeredchronically.

In another aspect, the present disclosure also provides a method oftreating the AXL kinase-related disease in a subject. The methodincludes administering to the subject a therapeutically effective amountof the compound disclosed herein In a specific embodiment, the diseaseis mediated by AXL. In a specific embodiment, the patient is diagnosedor identified as having an AXL-related cancer. In a specific embodiment,the disease is a cancer with high expression of AXL. In a specificembodiment, the disease is a cancer that has acquired resistance to theanti-cancer drug treatment due to AXL activation In a specificembodiment, the compound is administered orally, subcutaneously,intravenously or intramuscularly. In a specific embodiment, the compoundis administered chronically.

In another aspect, the present disclosure also provides a use of thecompound disclosed herein in the preparation of a medicament for thetreatment of AXL, kinase-related diseases. The method includesadministering to the subject a therapeutically effective amount of thecomp and disclosed herein In a specific embodiment, the disease ismediated by AXL. In a specific embodiment, the patient is diagnosed oridentified as having an AXL-related cancer. In a specific embodiment,the disease is a cancer with high expression of AXL. In a specificembodiment, the disease is a cancer that has acquired resistance to theanti-cancer drug treatment due to AXL activation. In a specificembodiment, the compound is administered orally, subcutaneously,intravenously or intramuscularly. In a specific embodiment, the compoundis administered chronically. Other objects and advantages of the presentdisclosure will be apparent to those skilled in the art from thesubsequent specific embodiments, examples and claims.

Definitions

As used herein, unless otherwise specified, “deuterated” means that oneor more hydrogens in a compound or group are substituted by deuterium;the “deuterated” may be mono-substituted, di-substituted,poly-substituted or fully-substituted by deuterium. The terms“substituted with one or more deuteriums” and “substituted one or moretimes by deuterium” are used interchangeably.

As used herein, unless otherwise specified, “non-deuterated compound”refers to a compound wherein the content of the deuterium atom is nothigher than the natural content of the deuterium isotope (0.015%).

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptablesalts of the compounds of the present disclosure include those derivedfrom suitable inorganic and organic acids and inorganic and organicbases.

Also disclosed herein are isotopically labeled compounds to the extentof the original compounds disclosed herein. Examples of isotopes thatcan be listed in compounds disclosed herein include hydrogen, carbon,nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes,such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl,respectively. A compound disclosed herein containing the above isotopeor other isotopic atoms, or an enantiomer, a diastereomer, an isomer, ora pharmaceutically acceptable salt or a solvate thereof are all withinthe scope disclosed herein. Certain isotopically labeled compoundsdisclosed herein, such as the radioisotopes of ³H and ¹⁴C, are alsoamong them and are useful in the tissue distribution experiments ofdrugs and substrates. Tritium, i.e., ³H, and carbon-14, i.e., ¹⁴C, areeasier to be prepared and detected and are the first choice forisotopes. Isotopically-labeled compounds can be prepared using theschemes shown in the Examples by conventional methods by replacing thenon-isotopic reagents with readily available isotopically labeledreagents.

The compound disclosed herein may include one or more asymmetriccenters, and thus may exist in a variety of “stereoisomer” forms, forexample, enantiomeric and/or diastereomeric forms. For example, thecompound disclosed herein may be in the form of an individualenantiomer, a diastereomer or a geometric isomer (e.g., cis- andtrans-isomers), or may be in the form of a mixture of stereoisomers,including a racemic mixture and a mixture enriched in one or morestereoisomers. The isomers can be separated from the mixture by methodsknown to those skilled in the art, including: chiral high pressureliquid chromatography (HPLC) and formation and crystallization of achiral salt; or preferred isomers can be prepared by asymmetricsynthesis.

The compound disclosed herein may be in an amorphous or a crystallineform. In addition, the compound disclosed herein may exist in one ormore crystalline forms. Therefore, the present disclosure includes allamorphous or crystalline forms of the compound disclosed herein withinits scope. The term “polymorph” refers to the different arrangement ofchemical drug molecules, which is generally presented as the existenceform of the drug raw materials in the solid state. A drug may exist in avariety of crystal forms, and different crystal forms of the same drugmay have different dissolution and absorption properties in vivo,thereby affecting the dissolution and release of the formulation.

The term “solvate” refers to a complex in which a compound disclosedherein coordinates with a solvent molecule in a particular ratio.“Hydrate” refers to a complex formed by coordination of a compounddisclosed herein with water.

The term “prodrug” as used herein refers to a compound, which isconverted in vivo to an active form thereof having a medical effect by,for example, hydrolysis in blood. Pharmaceutically acceptable prodrugsare described in T. Higuchi and V. Stella, Prodrugs as Novel DeliverySystems, A.C.S. Symposium Series Vol. 14, Edward B. Roche, ed.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H.Barbra “Improved oral drug delivery: solubility limitations overcome bythe use of prodrugs”, Advanced Drug Delivery Reviews (1996) 19(2)115-130, each of which is incorporated herein by reference.

A prodrug is any covalently bonded compound disclosed herein which, whenadministered to a patient, releases the parent compound in vivo. Aprodrug is typically prepared by modifying a functional group in such away that the modification can be cleaved either by routine manipulationor decompose in vivo to yield the parent compound. A prodrug includes,for example, a compound disclosed herein wherein a hydroxy, amino ormercapto group is bonded to any group which, when administered to apatient, can be cleaved to form a hydroxy, amino or mercapto group.Thus, representative examples of prodrugs include, but are not limitedto, the acetate/acetamide, formate/formamide and benzoate/benzamidederivatives of the hydroxyl, mercapto and amino functional groups of thecompound of formula (I). Further, in the case of a carboxylic acid(—COOH), an ester such as a methyl ester, an ethyl ester or the like maybe used. The ester itself may be active and/or may be hydrolyzed in vivounder human body conditions. Suitable pharmaceutically acceptable invivo hydrolysable esters include those, which readily decompose in ahuman body to release a parent acid or its salt.

The term “polymorph” refers to the different arrangement of chemicaldrug molecules, which is generally presented as the existence form ofthe drug raw materials in the solid state. A drug may exist in a varietyof crystal forms, and different crystal forms of the same drug may havedifferent dissolution and absorption properties in vivo, therebyaffecting the dissolution and release of the formulation.

As used herein, the term “subject” includes, but is not limited to,humans (i.e., a male or female of any age group, e.g., a pediatricsubject. (e.g, infant, child, adolescent) or adult subject (e.g., youngadult, middle-aged adult or senior adult)) and/or a non-human animal,e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesusmonkeys), cattle, pigs, horses, sheep, goats, rodents, cats and/or dogs.In certain embodiments, the subject is a human. In certain embodiments,the subject is a non-human animal.

“Disease”, “disorder” and “condition” are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat,”“treating,” and “treatment” contemplate an action that occurs while asubject is suffering from a particular disease, disorder, or condition,which reduces the severity of the disease, disorder or condition, orretards or slows the progression of the disease, disorder or condition(“therapeutic treatment”). The term also contemplates an action thatoccurs before a subject begins to suffer from a specific disease,disorder or condition (“prophylactic treatment”).

Generally, the “effective amount” of a compound refers to an amountsufficient to elicit a desired biological response. As will beappreciated by those skilled in the art, the effective amount of thecompound disclosed herein can vary depending on the following factors,such as the desired biological endpoint, the pharmacokinetics of thecompound, the diseases being treated, the mode of administration, andthe age, health status and symptoms of the subjects. The effectiveamount includes therapeutically effective amount and prophylacticallyeffective amount.

As used herein, and unless otherwise specified, the “therapeuticallyeffective amount” of the compound is an amount sufficient to providetherapeutic benefits in the course of treating a disease, disorder orcondition, or to delay or minimize one or more symptoms associated withthe disease, disorder or condition. The therapeutically effective amountof a compound refers to the amount of the therapeutic agent that, whenused alone or in combination with other therapies, provides atherapeutic benefit in the treatment of a disease, disorder orcondition. The term “therapeutically effective amount” can include anamount that improves the overall treatment, reduces or avoids thesymptoms or causes of the disease or condition, or enhances thetherapeutic effect of other therapeutic agents.

As used herein, and unless otherwise specified, the “prophylacticallyeffective amount” of the compound is an amount sufficient to prevent adisease, disorder or condition, or an amount sufficient to prevent oneor more symptoms associated with a disease, disorder or condition, or anamount sufficient to prevent the recurrence of a disease, disorder orcondition. The prophylactically effective amount of a compound refers tothe amount of a therapeutic agent that, when used alone or incombination with other agents, provides a prophylactic benefit in theprevention of a disease, disorder or condition. The term“prophylactically effective amount” can include an amount that improvesthe overall prevention, or an amount that enhances the prophylacticeffect of other preventive agents.

“Combination” and related terms refer to the simultaneous or sequentialadministration of the therapeutic agents disclosed herein. For example,the compounds of the present disclosure can be administeredsimultaneously or sequentially in separate unit dosage with othertherapeutic agents, or simultaneously in a single unit dosage with othertherapeutic agents.

DETAILED DESCRIPTION OF THE INVENTION Compounds

The present disclosure provides a compound of formula (Φ), or apharmaceutically acceptable salt, prodrug, hydrate, solvate, polymorph,stereoisomer or isotopic variant thereof:

wherein,

R¹, R², R³, R⁴, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³ and R²⁴ are independentlyselected from hydrogen or deuterium;

X¹ and X² are independently selected from CH₃, CD₃, CHD₂ or CH₂D;

X³ is selected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃, CHDCH₂D,CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ or CD₂CD₃;

Y¹, Y² and Y³ are independently selected from hydrogen or deuterium;

with the proviso that the compound described above contains at least onedeuterium atom.

As a specific embodiment of the present disclosure, the compound offormula (Φ) contains at least one deuterium atom, alternatively twodeuterium atoms, alternatively three deuterium atoms, alternatively fourdeuterium atoms, alternatively five deuterium atoms, alternatively sixdeuterium atoms, alternatively seven deuterium atoms, alternativelyeight deuterium atoms, alternatively nine deuterium atoms, alternativelyten deuterium atoms, alternatively eleven deuterium atoms, alternativelytwelve deuterium atoms, alternatively thirteen deuterium atoms,alternatively fourteen deuterium atoms, alternatively fifteen deuteriumatoms, alternatively sixteen deuterium atoms, alternatively seventeendeuterium atoms, alternatively eighteen deuterium atoms, alternativelynineteen deuterium atoms, alternatively twenty deuterium atoms,alternatively twenty-one deuterium atoms, alternatively twenty-twodeuterium atoms, alternatively twenty-three deuterium atoms,alternatively twenty-four deuterium atoms, alternatively twenty-fivedeuterium atoms, alternatively twenty-six deuterium atoms, alternativelytwenty-seven deuterium atoms, alternatively twenty-eight deuteriumatoms, alternatively twenty-nine deuterium atoms, alternatively thirtydeuterium atoms, alternatively thirty-one deuterium atoms, alternativelythirty-two deuterium atoms, alternatively thirty-three deuterium atoms,alternatively thirty-four deuterium atoms, alternatively thirty-fivedeuterium atoms, alternatively thirty-six deuterium atoms, alternativelythirty-seven deuterium atoms, and alternatively thirty-eight deuteriumatoms.

As an alternative embodiment of the present disclosure, the content ofdeuterium isotope in each deuterated position is at least greater thanthe natural content of deuterium isotope 0.015%, alternatively greaterthan 30%, alternatively greater than 50%, alternatively greater than75%, alternatively greater than 95%, and alternatively greater than 99%.

Specifically, in the present disclosure, the content of the deuteriumisotope in each deuterated position of R¹, R², R³, R⁴, R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹,R²², R²³, R²⁴, Y¹, Y², Y³, X¹, X² and X³ is at least 5%, alternativelygreater than 10%, alternatively greater than 15%, alternatively greaterthan 20%, alternatively greater than 25%, alternatively greater than30%, alternatively greater than 35%, alternatively greater than 40%,alternatively greater than 45%, alternatively greater than 50%,alternatively greater than 55%, alternatively greater than 60%,alternatively greater than 65%, alternatively greater than 70%,alternatively greater than 75%, alternatively greater than 80%,alternatively greater than 85%, alternatively greater than 90%,alternatively greater than 95%, and alternatively greater than 99%.

In another specific embodiment, among R¹, R², R³, R⁴, R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹,R²³, R²⁴, Y¹, Y², Y³, X¹, X² and X³ of the compound of formula (I), atleast one of them contains deuterium, alternatively two containdeuterium, alternatively three contain deuterium, alternatively fourcontain deuterium, alternatively five contain deuterium, alternativelysix contain deuterium, alternatively seven contain deuterium,alternatively eight contain deuterium, alternatively nine containdeuterium, alternatively ten contain deuterium, alternatively elevencontain deuterium, alternatively twelve contain deuterium, alternativelythirteen contain deuterium, alternatively fourteen contain deuterium,alternatively fifteen contain deuterium, alternatively sixteen containdeuterium, alternatively seventeen contain deuterium, alternativelyeighteen contain deuterium, alternatively nineteen contain deuterium,alternatively twenty contain deuterium, alternatively twenty-one containdeuterium, alternatively twenty-two contain deuterium, alternativelytwenty-three contain deuterium, alternatively twenty-four containdeuterium, alternatively twenty-five contain deuterium, alternativelytwenty-six contain deuterium, alternatively twenty-seven containdeuterium, alternatively twenty-eight contain deuterium, alternativelytwenty-nine contain deuterium, alternatively thirty contain deuterium,alternatively thirty-one contain deuterium, alternatively thirty-twocontain deuterium, alternatively thirty-three contain deuterium,alternatively thirty-four contain deuterium, alternatively thirty-fivecontain deuterium, alternatively thirty-six contain deuterium,alternatively thirty-seven contain deuterium, and alternativelythirty-eight contain deuterium. Specifically, the compound of formula(I) contains at least one, two, three, four, five, six, seven, eight,nine, ten. eleven, twelve, thirteen fourteen, fifteen, sixteen,seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two,twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven,twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three,thirty-four, thirty-five, thirty-six, thirty-seven and thirty-eightdeuterium atoms.

In another specific embodiment, “R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³ andR²⁴ are independently selected from hydrogen or deuterium” includes thetechnical solutions wherein, R¹ is selected from hydrogen or deuterium,R² is selected from hydrogen or deuterium, R³ is selected from hydrogenor deuterium and so on, until R²⁴ is selected from hydrogen ordeuterium. More specifically, the technical solutions wherein, R¹ ishydrogen or R¹ is deuterium, R² is hydrogen or R² is deuterium, R³ ishydrogen or R³ is deuterium and so on, until R²⁴ is hydrogen or R²⁴ isdeuterium, are included.

In another specific embodiment, “X¹ and X² are independently selectedfrom CH₃, CD₃, CHD₂ or CH₂D” includes the technical solutions wherein,X¹ is selected from CH₃, CD₃, CHD₂ or CH₂D, and X¹ is selected from CH₃,CD₃, CHD₂ or CH₂D. More specifically, the technical solutions wherein,X¹ is CH₃, X¹ is CD₃, X¹ is CHD₂ or X¹ is CH₂D, and X² is CH₃, X² isCD₃, X² is CHD₂ or X² is CH₂D, are included.

In another specific embodiment, “X³ is selected from CH₂CH₃, CH₂CH₂D,CH₂CHD₂, CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D,CD₂CHD₂ or CD₂CD₃” includes the technical solutions wherein, X³ isCH₂CH₃, X³ is CH₂CH₂D, X³ is CH₂CHD₂, X³ is CH₂CD₃, X³ is CHDCH₃, X³ isCHDCH₂D, X³ is CHDCHD₂, X³ is CHDCD₃, X³ is CD₂CH₃, X³ is CD₂CH₂D, X³ isCD₂CHD₂ or X³ is CD₂CD₃.

In another specific embodiment, “Y¹, Y² and Y³ are independentlyselected from hydrogen or deuterium” includes the technical solutionswherein, Y¹ is selected from hydrogen or deuterium, Y² is selected fromhydrogen or deuterium, and Y³ is selected from hydrogen or deuterium.More specifically, the technical solutions wherein, Y¹ is hydrogen or Y¹is deuterium, Y² is hydrogen or Y² is deuterium, and Y³ is hydrogen orY³ is deuterium, are included.

In another embodiment, the present disclosure relates to a compound offormula (I):

wherein,

R¹, R², R³, R⁴, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³ and R²⁴ are independentlyselected from hydrogen or deuterium:

X¹ and X² are independently selected from CH₃, CD₃, CHD₂ or CH₂D;

X³ is selected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃, CHDCH₂D,CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ or CD₂CD₃;

with the proviso that the compound described above contains at least onedeuterium atom;

or a pharmaceutically acceptable salt, prodrug, hydrate, solvate,polymorph, stereoisomer or isotopic variant thereof.

As a specific embodiment of the present disclosure, the compound offormula (I) contains at least one deuterium atom, alternatively onedeuterium atom, alternatively two deuterium atoms, alternatively threedeuterium atoms, alternatively four deuterium atoms, alternatively fivedeuterium atoms, alternatively six deuterium atoms, alternatively sevendeuterium atoms, alternatively eight deuterium atoms, alternatively ninedeuterium atoms, alternatively ten deuterium atoms, alternatively elevendeuterium atoms, alternatively twelve deuterium atoms, alternativelythirteen deuterium atoms, alternatively fourteen deuterium atoms,alternatively fifteen deuterium atoms, alternatively sixteen deuteriumatoms, alternatively seventeen deuterium atoms, alternatively eighteendeuterium atoms, alternatively nineteen deuterium atoms, alternativelytwenty deuterium atoms, alternatively twenty-one deuterium atoms,alternatively twenty-two deuterium atoms, alternatively twenty-threedeuterium atoms, alternatively twenty-four deuterium atoms,alternatively twenty-five deuterium atoms, alternatively twenty-sixdeuterium atoms, alternatively twenty-seven deuterium atoms,alternatively twenty-eight deuterium atoms, alternatively twenty-ninedeuterium atoms, alternatively thirty deuterium atoms, alternativelythirty-one deuterium atoms, alternatively thirty-two deuterium atoms,alternatively thirty-three deuterium atoms, alternatively thirty-fourdeuterium atoms, and alternatively thirty-five deuterium atoms.

As an alternative embodiment of the present disclosure, the content ofdeuterium isotope in each deuterated position is at least greater thanthe natural content of deuterium isotope 0.015%, alternatively greaterthan 30%, alternatively greater than 50%, alternatively greater than75%, alternatively greater than 95%, and alternatively greater than 99%.

Specifically, in the present disclosure, the content of the deuteriumisotope in each deuterated position of R¹, R², R³, R⁴, R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹,R²², R²³, R²⁴, X¹, X², and X³ is at least 5%, alternatively greater than10%, alternatively greater than 15%, alternatively greater than 20%,alternatively greater than 25%, alternatively greater than 30%,alternatively greater than 35%, alternatively greater than 40%,alternatively greater than 45%, alternatively greater than 50%,alternatively greater than 55%, alternatively greater than 60%,alternatively greater than 65%, alternatively greater than 70%,alternatively greater than 75%, alternatively greater than 80%,alternatively greater than 85%, alternatively greater than 90%,alternatively greater than 95%, and alternatively greater than 99%.

In another specific embodiment, among R¹, R², R³, R⁴, R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹,R²², R²³, R²⁴, X¹, X² and X³ of the compound of formula (I), at leastone of them contains deuterium, alternatively two contain deuterium,alternatively three contain deuterium, alternatively four containdeuterium, alternatively five contain deuterium, alternatively sixcontain deuterium, alternatively seven contain deuterium, alternativelyeight contain deuterium, alternatively nine contain deuterium,alternatively ten contain deuterium, alternatively eleven containdeuterium, alternatively twelve contain deuterium, alternativelythirteen contain deuterium, alternatively fourteen contain deuterium,alternatively fifteen contain deuterium, alternatively sixteen containdeuterium, alternatively seventeen contain deuterium, alternativelyeighteen contain deuterium, alternatively nineteen contain deuterium,and alternatively twenty contain deuterium. Specifically, the compoundof formula (I) contains at least one, two, three, four, five, six,seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen,sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two,twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven,twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three,thirty-four, thirty-five, thirty-six, thirty-seven and thirty-eightdeuterium atoms.

As a specific embodiment of the present disclosure, X¹ and X² areindependently selected from CH₃, CD₃, CHD₂ or CH₂D. In another specificembodiment, X¹ and X² are independently selected from CH₃ or CD₃. Inanother specific embodiment, X¹ is CH₃. In another specific embodiment,X¹ is CD₃. In another specific embodiment, X² is CH₃. In anotherspecific embodiment, X² is CD₃. In another specific embodiment, X¹ andX² are the same. In another embodiment, X¹ and X² are different.

As a specific embodiment of the present disclosure, X³ is selected fromCH₂CH₃, CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃,CD₂CH₃, CD₂CH₂D, CD₂CHD₂ or CD₂CD₃. In another specific embodiment, X³is selected from CH₂CH₃ or CD₂CD₃. In another specific embodiment. X³ isCH₂CH₃. In another specific embodiment, X³ is CD₂CD₃.

As a specific embodiment of the present disclosure, R¹, R², R³, R⁴, R⁵,R⁶, R⁷ and R⁸ are independently selected from hydrogen or deuterium. Inanother specific embodiment, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are thesame. In another specific embodiment, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸are hydrogen. In another specific embodiment, R¹, R², R³, R⁴, R⁵, R⁶, R⁷and R⁸ are deuterium.

As a specific embodiment of the present disclosure, R⁹, R¹⁰, R¹¹, R¹²,R¹³, R¹⁴, R¹⁵ and R¹⁶ are independently selected from hydrogen ordeuterium. In another specific embodiment. R⁹, R¹⁰, R¹¹ and R¹² are thesame, and R¹³, R¹⁴, R¹⁵ and R¹⁶ are the same. In another specificembodiment, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are hydrogen. Inanother specific embodiment, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶are deuterium. In another specific embodiment, R⁹, R¹⁰, R¹¹ and R¹² aredeuterium, and R¹³, R¹⁴, R¹⁵ and R¹⁶ are hydrogen. In another specificembodiment, R⁹, R¹⁰, R¹¹ and R¹² are hydrogen, and R¹³, R¹⁴, R¹⁵ and R¹⁶are deuterium.

In a specific embodiment, the present disclosure relates to a compoundof formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate,solvate, polymorph, stereoisomer or isotopic variant thereof, wherein,R⁹ to R¹² are hydrogen, R¹ to R⁸ are independently selected fromhydrogen or deuterium, R¹³ to R²⁴ are independently selected fromhydrogen or deuterium, X¹ and X² are independently selected from CH₃,CD₃, CHD₂ or CH₂D, X³ is selected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂, CH₂CD₃,CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ or CD₂CD₃,with the proviso that the compound described above contains at least onedeuterium atom.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, R¹ to R⁸ are hydrogen, R⁹ to R²⁴ are independently selectedfrom hydrogen or deuterium, X¹ and X² are independently selected fromCH₃, CD₃, CHD₂ or CH₂D, X³ is selected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂,CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ orCD₂CD₃, with the proviso that the compound described above contains atleast one deuterium atom.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, R¹ to R¹² are hydrogen, R¹³ to R²⁴ are independently selectedfrom hydrogen or deuterium, X¹ and X² are independently selected fromCH₃, CD₃, CHD₂ or CH₂D, X³ is selected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂,CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ orCD₂CD₃, with the proviso that the compound described above contains atleast one deuterium atom.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X² is CD₃, R¹ to R²⁴ are independently selected from hydrogenor deuterium, X¹ is selected from CH₃, CD₃, CHD₂ or CH₂D, X³ is selectedfrom CH₂CH₃, CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃,CD₂CH₃, CD₂CH₂D, CD₂CHD₂ or CD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X² is CD₃, R⁹ to R¹² are hydrogen, R¹ to R⁸ are independentlyselected from hydrogen or deuterium, R¹³ to R²⁴ are independentlyselected from hydrogen or deuterium, X¹ is selected from CH₃, CD₃, CHD₂or CH₂D, X³ is selected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃,CHDCH₂D, CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ or CD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X² is CD₃, R¹ to R⁸ are hydrogen, R⁹ to R²⁴ are independentlyselected from hydrogen or deuterium, X¹ is selected from CH₃, CD₃, CHD₂or CH₂D, X³ is selected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃,CHDCH₂D, CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ or CD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X² is CD₃. R¹ to R¹² are hydrogen, R¹³ to R²⁴ are independentlyselected from hydrogen or deuterium, X¹ is selected from CH₃, CD₃, CHD₂or CH₂D, X³ is selected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃,CHDCH₂D, CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ or CD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X¹ is CD₃, R¹ to R²⁴ are independently selected from hydrogenor deuterium, X² is selected from CH₃, CD₃, CHD₂ or CH₂D, X³ is selectedfrom CH₂CH₃, CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃,CD₂CH₃, CD₂CH₂D, CD₂CHD₂ or CD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X¹ is CD₃, R⁹ to R¹² are hydrogen, R¹ to R⁸ are independentlyselected from hydrogen or deuterium, R¹³ to R²⁴ are independentlyselected from hydrogen or deuterium, X² is selected from CH₃, CD₃, CHD₂or CH₂D, X³ is selected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃,CHDCH₂D, CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ or CD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X¹ is CD₃, R¹ to R⁸ are hydrogen, R⁹ to R²⁴ are independentlyselected from hydrogen or deuterium, X² is selected from CH₃, CD₃, CHD₂or CH₂D, X³ is selected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃,CHDCH₂D, CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ or CD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X¹ is CD₃, R¹ to R¹² are hydrogen, R¹³ to R²⁴ are independentlyselected from hydrogen or deuterium, X² is selected from CH₃, CD₃, CHD₂or CH₂D, X³ is selected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃,CHDCH₂D, CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ or CD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X¹ and X² are CD₃, R¹ to R²⁴ are independently selected fromhydrogen or deuterium, X³ is selected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂,CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ orCD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X¹ and X² are CD₃, R⁹ to R¹² are hydrogen, R¹ to R⁸ areindependently selected from hydrogen or deuterium, R¹³ to R²⁴ areindependently selected from hydrogen or deuterium, X³ is selected fromCH₂CH₃, CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCD₃, CD₂CH₃,CD₂CH₂D, CD₂CHD₂ or CD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X¹ and X² are CD₃, R¹ to R⁸ are hydrogen, R⁹ to R²⁴ areindependently selected from hydrogen or deuterium, X³ is selected fromCH₂CH₃, CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃,CD₂CH₃, CD₂CH₂D, CD₂CHD₂ or CD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X¹ and X² are CD₃, R¹ to R¹² are hydrogen, R¹³ to R²⁴ areindependently selected from hydrogen or deuterium, X³ is selected fromCH₂CH₃, CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃,CD₂CH₃, CD₂CH₂D, CD₂CHD₂ or CD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X³ is CD₂CD₃, R¹ to R²⁴ are independently selected fromhydrogen or deuterium, X¹ and X² are independently selected from CH₃,CD₃, CHD₂ or CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X³ is CD₂CD₃, R⁹ to R¹² are hydrogen, R¹ to R⁸ areindependently selected from hydrogen or deuterium, R¹³ to R²⁴ areindependently selected from hydrogen or deuterium, X¹ and X² areindependently selected from CH₃, CD₃, CHD₂ or CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X³ is CD₂CD₃, R¹ to R⁸ are hydrogen, R⁹ to R²⁴ areindependently selected from hydrogen or deuterium, X¹ and X² areindependently selected from CH₃, CD₃, CHD₂ or CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X³ is CD₂CD₃, R¹ to R¹² are hydrogen, R¹³ to R²⁴ areindependently selected from hydrogen or deuterium, X¹ and X² areindependently selected from CH₃, CD₃, CHD₂ or CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X³ is CD₂CD₃, X² is CD₃, R¹ to R²⁴ are independently selectedfrom hydrogen or deuterium, X¹ is selected from CH₃, CD₃, CHD₂ or CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X² is CD₃, X³ is CD₂CD₃, R⁹ to R¹² are hydrogen, R¹ to R⁸ areindependently selected from hydrogen or deuterium, R¹³ to R²⁴ areindependently selected from hydrogen or deuterium, X¹ is selected fromCH₃, CD₃, CHD₂ or CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X² is CD₃, X³ is CD₂CD₃, R¹ to R⁸ are hydrogen, R⁹ to R²⁴ areindependently selected from hydrogen or deuterium, X¹ is selected fromCH₃, CD₃, CHD₂ or CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X¹ is CD₃, X³ is CD₂CD₃, R¹ to R¹² are hydrogen, R¹³ to R²⁴ areindependently selected from hydrogen or deuterium, X¹ is selected fromCH₃, CD₃, CHD₂ or CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X¹ is CD₃, X³ is CD₂CD₃, R¹ to R²⁴ are independently selectedfrom hydrogen or deuterium. X² is selected from CH₃, CD₃, CHD₂ or CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X¹ is CD₃, X³ is CD₂CD₃, R³ to R¹² are hydrogen, R¹ to R⁸ areindependently selected from hydrogen or deuterium, R¹³ to R²⁴ areindependently selected from hydrogen or deuterium, X² is selected fromCH₃, CD₃, CHD₂ or CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X¹ is CD₃, X³ is CD₂CD₃, R¹ to R⁸ are hydrogen, R⁹ to R²⁴ areindependently selected from hydrogen or deuterium, X² is selected fromCH₃, CD₃, CHD₂ or CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X¹ is CD₃, X³ is CD₂CD₃, R¹ to R¹² are hydrogen, R¹³ to R²⁴ areindependently selected from hydrogen or deuterium, X² is selected fromCH₃, CD₃, CHD₂ or CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X¹ and X² are CD₃, X³ is CD₂CD₃, R¹ to R²⁴ are independentlyselected from hydrogen or deuterium.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X¹ and X² are CD₃, X³ is CD₂CD₃, R⁹ to R¹² are hydrogen, R¹ toR⁸ are independently selected from hydrogen or deuterium, R¹³ to R²⁴ areindependently selected from hydrogen or deuterium.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X¹ and X² are CD₃, X³ is CD₂CD₃, R¹ to R⁸ are hydrogen, R⁹ toR²⁴ are independently selected from hydrogen or deuterium.

In another specific embodiment, the present disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, X¹ and X² are CD₃, X³ is CD₂CD₃, R¹ to R¹² are hydrogen, R²³ toR²⁴ are independently selected from hydrogen or deuterium.

In another embodiment, the present disclosure relates to a compound offormula (II):

wherein,

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are independentlyselected from hydrogen or deuterium;

X¹ and X² are independently selected from CH₃, CD₃, CHD₂ or CH₂D;

X³ is selected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃, CHDCH₂D,CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ or CD₂CD₃;

with the proviso that the compound described above contains at least onedeuterium atom;

or a pharmaceutically acceptable salt, prodrug, hydrate, solvate,polymorph, stereoisomer or isotopic variant thereof.

In a specific embodiment, the present disclosure relates to a compoundof formula (II), or a pharmaceutically acceptable salt, prodrug,hydrate, solvate, polymorph, stereoisomer or isotopic variant thereof,wherein, R⁹ to R¹² are hydrogen, R¹ to R⁸ are independently selectedfrom hydrogen or deuterium, X¹ and X² are independently selected fromCH₃, CD₃, CHD₂ or CH₂D, X³ is selected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂,CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ orCD₂CD₃, with the proviso that the compound described above contains atleast one deuterium atom.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, R¹ to R⁸ are hydrogen, R⁹ to R¹² are independentlyselected from hydrogen or deuterium, X¹ and X² are independentlyselected from CH₃, CD₃, CHD₂ or CH₂D, X³ is selected from CH₂CH₃,CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃, CD₂CH₃,CD₂CH₂D, CD₂CHD₂ or CD₂CD₃, with the proviso that the compound describedabove contains at least one deuterium atom.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, R¹ to R¹² are hydrogen, X¹ and X² are independentlyselected from CH₃, CD₃, CHD₂ or CH₂D, X³ is selected from CH₂CH₃,CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃, CD₂CH₃,CD₂CH₂D, CD₂CHD₂ or CD₂CD₃, with the proviso that the compound describedabove contains at least one deuterium atom.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X² is CD₃, R¹ to R¹² are independently selected fromhydrogen or deuterium, X¹ is selected from CH₃, CD₃, CHD₂ or CH₂D, X³ isselected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃, CHDCH₂D,CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ or CD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X² is CD₃, R⁹ to R¹² are hydrogen, R¹ to R⁸ areindependently selected from hydrogen or deuterium, X¹ is selected fromCH₃, CD₃, CHD₂ or CH₂D, X³ is selected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂,CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ orCD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X² is CD₃, R¹ to R⁸ are hydrogen, R⁹ to R¹² areindependently selected from hydrogen or deuterium, X¹ is selected fromCH₃, CD₃, CHD₂ or CH₂D, X¹ is selected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂,CH₂CD₃, CHDCH₃, CHDCH₂D, CRDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ orCD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X² is CD₃, R¹ to R¹² are hydrogen, X¹ is selected fromCH₃, CD₃, CHD₂ or CH₂D, X³ is selected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂,CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ orCD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X¹ is CD₃, R¹ to R¹² are independently selected fromhydrogen or deuterium, X² is selected from CH₃, CD₃, CHD₂ or CH₂D, X³ isselected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃, CHDCH₂D,CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ or CD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X¹ is CD₃, R⁹ to R¹² are hydrogen, R¹ to R⁸ areindependently selected from hydrogen or deuterium, X² is selected fromCH₃, CD₃, CHD₂ or CH₂D, X³ is selected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂,CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ orCD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X¹ is CD₃, R¹ to R⁸ are hydrogen, R⁹ to R¹² areindependently selected from hydrogen or deuterium. X² is selected fromCH₃, CD₃, CHD₂ or CH₂D, X³ is selected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂,CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ orCD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X¹ is CD₃, R¹ to R¹² are hydrogen, X² is selected fromCH₃, CD₃, CHD₂ or CH₂D, X³ is selected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂,CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ orCD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X¹ and X² are CD₃, R¹ to R¹² are independentlyselected from hydrogen or deuterium, X³ is selected from CH₂CH₃,CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃, CD₂CH₃,CD₂CH₂D, CD₂CHD₂ or CD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X¹ and X² are CD₃, R⁹ to R¹² are hydrogen, R¹ to R⁸are independently selected from hydrogen or deuterium, X³ is selectedfrom CH₂CH₃, CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃,CD₂CH₃, CD₂CH₂D, CD₂CHD₂ or CD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein X¹ and X² are CD₃, R¹ to R⁸ are hydrogen, R⁹ to R¹² areindependently selected from hydrogen or deuterium, X³ is selected fromCH₂CH₃, CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃,CD₂CH₃, CD₂CH₂D, CD₂CHD₂ or CD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X¹ and X² are CD₃, R¹ to R¹² are hydrogen, X³ isselected from CH₂CH₃, CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃, CHDCH₂D,CHDCHD₂, CHDCD₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂ or CD₂CD₃.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X³ is CD₂CD₃, R¹ to R¹² are independently selectedfrom hydrogen or deuterium, X¹ and X² are independently selected fromCH₃, CD₃, CHD₂ or CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X³ is CD₂CD₃, R⁹ to R¹² are hydrogen, R¹ to R⁸ areindependently selected from hydrogen or deuterium, X¹ and X² areindependently selected from CH₃, CD₃, CHD₂ or CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X³ is CD₂CD₃, R¹ to R⁸ are hydrogen, R⁹ to R¹² areindependently selected from hydrogen or deuterium, X¹ and X² areindependently selected from CH₃, CD₃, CHD₂ or CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X³ is CD₂CD₃, R¹ to R¹² are hydrogen, X¹ and X² areindependently selected from CH₃, CD₃, CHD₂ or CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X³ is CD₂CD₃, X² is CD₃, R¹ to R¹² are independentlyselected from hydrogen or deuterium, X¹ is selected from CH₃, CD₃, CHD₂or CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X² is CD₃, X³ is CD₂CD₃, R⁹ to R¹² are hydrogen, R¹ toR⁸ are independently selected from hydrogen or deuterium, X¹ is selectedfrom CH₃, CD₃, CHD₂ or CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X² is CD₃, X³ is CD₂CD₃, R¹ to R⁸ are hydrogen, R⁹ toR¹² are independently selected from hydrogen or deuterium, X¹ isselected from CH₃, CD₃, CHD₂ or CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X² is CD₃, X³ is CD₂CD₃, R¹ to R¹² are hydrogen, X¹ isselected from CH₃, CD₃, CHD₂ er CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X¹ is CD₃, X³ is CD₂CD₃, R¹ to R¹² are independentlyselected from hydrogen or deuterium, X² is selected from CH₃, CD₃, CHD₂or CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X¹ is CD₃, X³ is CD₂CD₃, R⁹ to R¹² are hydrogen, R¹ toR⁸ are independently selected from hydrogen or deuterium, X² is selectedfrom CH₃, CD₃, CHD₂ or CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X¹ is CD₃, X³ is CD₂CD₃, R¹ to R⁸ are hydrogen, R⁹ toR¹² are independently selected from hydrogen or deuterium, X² isselected front CH₃, CD₃, CHD₂ or CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X¹ is CD₃, X³ is CD₂CD₃, R¹ to R¹² are hydrogen, X² isselected from CH₃, CD₃, CHD₂ or CH₂D.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X¹ and X² are CD₃, X³ is CD₂CD₃, R¹ to R¹² areindependently selected from hydrogen or deuterium.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X¹ and X² are CD₃, X³ is CD₂CD₃, R⁹ to R¹² arehydrogen, R¹ to R⁸ are independently selected from hydrogen ordeuterium.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X¹ and X² are CD₃, X³ is CD₂CD₃, R¹ to R⁸ arehydrogen, R⁹ to R¹² are independently selected from hydrogen ordeuterium.

In another specific embodiment, the present disclosure relates to acompound of formula (II), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof, wherein, X¹ and X² are CD₃, X³ is CD₂CD₃, R¹ to R¹² arehydrogen.

As an alternative embodiment of the present disclosure, the compound isselected from the following group of compounds:

As an alternative embodiment of the present disclosure, the compounds donot include the non-deuterated compounds.

Pharmaceutical Compositions and Methods of Administration

In another aspect, provided herein is a pharmaceutical compositioncomprising the compound disclosed herein (also referred to as “activecomponent”) and pharmaceutically acceptable excipient(s). In someembodiments, the pharmaceutical composition comprises an effectiveamount of the active component. In some embodiments, the pharmaceuticalcomposition comprises a therapeutically effective amount of the activecomponent. In some embodiments, the pharmaceutical composition comprisesa prophylactically effective amount of the active component.

The pharmaceutical composition disclosed herein comprises a safe andeffective amount of the compound disclosed herein, or apharmacologically acceptable salt thereof, and pharmacologicallyacceptable excipient(s) or carrier(s). By “safe and effective amount” itis meant that the amount of the compound is sufficient to significantlyimprove the condition without causing serious side effects. In general,the pharmaceutical composition contains from 0.5 to 2000 mg of thecompound disclosed herein per dose, more preferably from 1 to 500 mg ofthe compound disclosed herein per dose. Preferably, the “one dose” isone capsule or tablet.

The “pharmaceutically acceptable excipient” refers to a non-toxiccarrier, adjuvant or vehicle that does not destroy the pharmacologicalactivity of the compound formulated together. Pharmaceuticallyacceptable carriers, adjuvants, or vehicles that can be used in thecompositions disclosed herein include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g.,human serum albumin), buffer substances (such as phosphate), glycine,sorbic acid, potassium sorbate, a mixture of partial glycerides ofsaturated plant fatty acids, water, salt or electrolyte (such asprotamine sulfate), disodium hydrogen phosphate, potassium hydrogenphosphate, sodium chloride, zinc salt, silica gel, magnesiumtrisilicate, polyvinyl pyrrolidone, cellulose-based substances,polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax,polyethylene-polyoxypropylene block polymer, polyethylene glycol andlanolin.

The pharmaceutical composition disclosed herein can be prepared bycombining the compound disclosed herein with suitable pharmaceuticallyacceptable excipient(s), for example, as a solid, semi-solid, liquid orgaseous preparation such as tablets, pills, capsules, powders, granules,ointments, emulsions, suspensions, solutions, suppositories, injections,inhalants, gels, microspheres, aerosols and the like.

Typical routes of administration of the compound disclosed herein or apharmaceutical composition thereof include, but are not limited to,oral, rectal, transmucosal, enteral administration, or topical,transdermal, inhalation, parenteral, sublingual, intravaginal,intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous,intravenous administration.

The pharmaceutical composition disclosed herein can be produced by amethod well known in the art, such as a conventional mixing method, adissolution method, a granulation method, a sugarcoating pill method, agrinding method, an emulsification method, a freeze drying method, andthe like.

For oral administration, the pharmaceutical composition can beformulated by mixing the active compound with pharmaceuticallyacceptable excipient(s) which are well known in the art. Theseexcipients enable the compound disclosed herein to be formulated intotablets, pills, troches, dragees, capsules, liquids, gels, slurries,suspensions and the like for oral administration to a patient.

A solid oral composition can be prepared by a conventional mixing,filling or tabletting method. For example, it can be obtained by mixingthe active compound with solid excipient(s), optionally milling theresulting mixture, adding other suitable adjuvant(s) if necessary, andthen processing the mixture into granules, thereby obtaining a tablet ora core of dragee. Suitable excipients include, but are not limited to,binders, diluents, disintegrants, lubricants, glidants, sweeteners orflavoring agents, and the like, such as microcrystalline cellulose,glucose solution, acacia mucilage, gelatin solution, sucrose and starchpaste; talc, starch, calcium stearate or stearic acid; lactose, sucrose,starch, mannitol, sorbitol or dicalcium phosphate; silica, cross-linkedhydroxy methylcellulose sodium, pregelatinized starch, sodium starchglycolate, alginic acid, corn starch, potato starch, methyl cellulose,agar, hydroxymethyl cellulose, cross-linked polyvinyl pyrrolidone andthe like. The core of the dragee may optionally be coated according tomethods well known in the ordinary pharmaceutical practice, especiallyusing enteric coatings.

The pharmaceutical compositions may also be suitable for parenteraladministration, such as sterile solutions, suspensions or lyophilizedproducts in a suitable unit dosage form. Suitable excipients such asfillers. buffers or surfactants can be used.

The compounds disclosed herein may be administered by any route andmethod of administration, for example by oral or parenteral (e.g.,intravenous) administration. A therapeutically effective amount of thecompound disclosed herein is from about 0.0001 to 20 mg/kg body weightper day, such as from 0.001 to 10 mg/kg body weight per day.

The dosing frequency of the compounds disclosed herein is determined bythe needs of the individual patient, for example, once or twice daily,or more times per day. Administration may be intermittent, for example,wherein the patient receives a daily dose of the compound disclosedherein for a period of several days, and then the patient does notreceive a daily dose of the compound disclosed herein for a period ofseveral days or more.

Therapeutic Indications of the Compound Disclosed Herein

The compound of the present disclosure shows the inhibitory effectagainst FLT3 protein tyrosine kinase, and can be used in the treatmentof FLT3-mediated diseases.

In some embodiments, the present disclosure provides a method oftreating the FLT3 kinase-mediated disease in a subject. The methodcomprises administering to the subject a therapeutically effectiveamount of the compound disclosed herein. In a specific embodiment, thedisease is mediated by FLT3. In a specific embodiment, the patient isdiagnosed or identified as having an FLT3-related cancer. In a specificembodiment, the compound is administered orally, subcutaneously,intravenously or intramuscularly. In a specific embodiment, the compoundis administered chronically. In a specific embodiment. the FLT3-mediateddisease is AML.

In some embodiments, the present disclosure provides a method oftreating AXL-related cancer. The method comprises administering to thesubject a therapeutically effective amount of the compound disclosedherein. AXL is a receptor-type tyrosine kinase, and is a protein havinga cell transmembrane domain in the center, a tyrosine kinase domain onthe carboxy-terminal side, and an extracellular domain on theamino-terminal side. AXL-related cancer refers to the cancer wherein oneof the causes thereof is AXL. As cancers with highly expressed AXL,examples such as AML, astrocytoma, breast cancer, colorectal cancer,gastrointestinal stromal tumor, gastric cancer, hepatocellularcarcinoma, Kaposi's sarcoma, lung cancer, melanoma, ovarian cancer,osteosarcoma, pancreatic ductal adenocarcinoma, renal cell carcinoma,prostate cancer, thyroid cancer, and endometrial cancer, in which AXL isoverexpressed compared to normal tissues, can be listed.

Compared with the non-deuterated compounds known in the prior art, thecompounds of the present disclosure have a series of advantages. Theadvantages of the present disclosure include: first, the compounds andcompositions of the technical solutions disclosed herein provide a moreadvantageous therapeutic tool for the treatment of AML, especially forthe treatment of FLT3- and AXL-related AML. Second, the metabolism ofthe compound in the organism is improved, allowing the compound to havebetter pharmacokinetic parameters. In this case, the dose may be changedand a long-acting formulation may be formed to improve theapplicability. Third, the drug concentration of the compound in animalsis increased, so that the efficacy of the drug is improved. Fourth, thesafety of the compound may be increased due to the inhibition of certainmetabolites.

EXAMPLES

The present disclosure is further illustrated below in conjunction withspecific examples. It is to be understood that the examples are used toillustrate the present disclosure, and not intended to limit the scopeof present disclosure. In the following examples, the experimentalmethods wherein the particular conditions are not specified are usuallyin accordance with conventional conditions or according to theconditions recommended by the manufacturer. Parts and percentages areparts by weight and percentage by weight unless otherwise stated.

Usually, in the preparation process, each reaction is usually carriedout in an inert solvent at room temperature to reflux temperature (e.g.,0° C. to 100° C., preferably 0° C. to 80° C.). The reaction time isusually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.

Example 1 Preparation of6-ethyl-3-((3-(methoxy-d₃)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide(Compound T-1)

The following route was used for the synthesis:

Step 1 Synthesis of Compound 2

Acetonitrile (30 mL) and 5-fluoro-2-nitrophenol (compound 1) (2.0 g,12.7 mmol) were sequentially added into a 100 mL single-necked flaskequipped with a magnetic stirrer. The resulting mixture was stirred toform a solution, after which anhydrous potassium carbonate (3.5 g, 25.4mmol) and deuterated methyl p-toluenesulfonate (3.12 g, 16.5 mmol) wereadded. The mixture was heated to 60° C. under nitrogen, stirred andreacted for 2 hours at this temperature. After cooling to roomtemperature, the solvent was evaporated under reduced pressure, andwater (20 mL) was added. Ethyl acetate (30 mL×3) was added forextraction. The organic phases were combined, and dried over anhydroussodium sulfate. After the filtration, the filtrate was concentrated togive 2.0 g of a white solid, with a yield of 90%. LC-MS(APCI):m/z=1.75.2(M+1)⁺.

Step 2 Synthesis of Compound 4

Acetonitrile (20 mL) and compound 2 (1.74 g, 10 mmol) were added into a50 mL single-necked flask equipped with a magnetic stirrer and acondenser. The resulting mixture was stirred to form a solution, afterwhich compound 3 (2.2 g, 12 mmol) and potassium carbonate (2.1 g, 15mmol) were added under stirring. The mixture was heated to 60° C. undernitrogen, stirred and reacted for 2 hours at this temperature. Aftercooling to room temperature, the solvent was evaporated under reducedpressure. Water (60 mL) was added, and a large amount of yellow solidwas precipitated out. After the filtration, the residue was washed withwater (20 mL), and dried to give 2.6 g of a yellow solid, with a yieldof 77.1%. LC-MS(APCI): m/z=338.2(M+1)⁺.

Step 3 Synthesis of Compound 5

Compound 4 (1.34 g, 4.0 mmol) and methanol (20 mL) were added into a 50mL single-necked flask equipped with a magnetic stirrer, and stirred toform a solution. Pd/C (0.12 g, 10%) was added, and the resulting mixturewas vacuumed and purged with hydrogen for three times, and stirred andreacted overnight at room temperature under a hydrogen balloon.Dichloromethane (30 mL) was added, and the catalyst was filtered off.The catalyst was washed with dichloromethane (5 mL), and the filtratewas concentrated under reduced pressure to give 1.18 g of a light brownsolid, with a yield of 98.2%. LC-MS(APCI): m/z=308.2(M+1)⁺.

Step 4 Synthesis of Compound 7

Compound 5 (0.62 g, 2.0 mmol) and 1,4-dioxane (10 mL) were added into a50 mL single-necked flask equipped with a magnetic stirrer and acondenser. The resulting mixture was stirred to form a solution, afterwhich compound 6 (0,50 g, 2.28 mmol) and DIPEA(N,N-diisopropylethylamine, 0.8 mL, 5.0 mmol) were added. The mixturewas heated to 110° C. under nitrogen, stirred and reacted overnight atthis temperature. The solvent was evaporated by concentrating underreduced pressure, and the residue was purified by silica gel columnchromatography to give 0.82 g of a yellow solid, with a yield of 83.7%.LC-MS(APCI): m/z=491.3(M+1)⁺. ¹H NMR(500 MHz, CDCl₃) δ (ppm):10.75(s,1H), 7.72(s, 1H), 7.35(d, J=2.0 Hz, 1H), 7.13(dd, J=9.5 Hz, J=2.0 Hz,1H), 6.88(d, J=9.5 Hz, 1H), 5.55(s, 1H), 3.53(d, J=11.5 Hz, 2H),2.99-2.75(m, 10H), 2.57(t, J=11.5 Hz, 2H), 2.49(s, 3H), 2.05-1.95(m,21-1), 1.90-1.82(m, 2H), 1.27(t, J=7.0 Hz, 3H).

Step 5 Synthesis of Compound T-1

Compound 7 (0.20 g, 0.41 mmol) and DMF (5 mL) were added into a 10 mLmicrowave reaction tube. The resulting mixture was stirred to form asolution, after which compound 8 (0.41 g, 4.1 mmol) and potassiumcarbonate (0.18 g, 1.21 mmol) were added. The mixture was heated to1150° C. in a microwave reactor, and reacted for 2 hours at thistemperature. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography to give 0.16 gof a yellow solid, with a yield of 70.3%. LC-MS(APCI): m/z=556.3(M+1)⁺.¹H NMR(400 MHz, CDCl₃) δ (ppm):10.69(s, 1H), 7.53-7.46(m, 2H), 6.91(d,J=2.4 Hz, 1H), 6.83(d, J=8.8 Hz, 1H), 5.17(br s, 1H), 4.62(d, J=7.2 Hz,1H), 4.29-4.15(m, 1H), 4.14-4.01(m, 2H), 3.57-3.51(m, 4H), 3.15-2.75(m,8H), 2.62-2.49(m, 7H), 2.10-1.98(m, 4H), 1.88-1.85(m, 2H), 1.62-1.60(m,2H), 1.34-1.29(m, 3H).

Example 2 Preparation of6-ethyl-3-((3-methoxy-4-(4-(4-(methyl-d₃)piperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide(Compound T-2)

The following route was used for the synthesis:

Step 1 Synthesis of Compound 10

Solid sodium hydroxide (11.2 g, 0.28 mol) was slowly added to water (100mL) under stirring, which was stirred to form a solution. The resultingmixture was cooled to below 10° C. in an ice-water bath, and compound 9(50 g, 0.27 mol) was added. A solution of methyl-d₃ p-toluenesulfonate(53.32 g, 0.28 mol) in acetone (250 mL) was slowly added dropwise,stirred, and, reacted overnight at room temperature. Di-tert-butyldicarbonate (3.42 g, 0.013 mol) was added to the reaction solution, andfurther stirred and reacted for 1 h. Acetone was evaporated underreduced pressure at room temperature, and the residue was extracted withethyl acetate (150 mL×3). The organic phases were combined, washed withwater (50 mL×3), saturated sodium carbonate (50 mL), saturated brine (50mL), and dried over anhydrous sodium sulfate. After the filtration, thefiltrate was concentrated under reduced pressure to approximately 250mL, and cooled in an ice-water bath. A solution of hydrogen chloride inisopropanol (5 M) was slowly added dropwise, during which thetemperature was controlled below 10° C. The pH was adjusted to 4, and alarge amount of white solid was generated. After stirring for half anhour under nitrogen, the resulting mixture was filtered. The filter cakewas washed with ethyl acetate (50 mL), and dried in vacuum to give 38 gof a white solid, with a yield of 61.6%. ¹H NMR(400 MHz, DMSO-d6) δ(ppm): 11.45(br s, 1H), 3.97-3.95(m, 2H), 3.33-3.29(m, 4H), 2.95-2.93(m,2H), 1.41(s, 9H).

Step 2 Synthesis of Compound 11

A solution of hydrogen chloride in isopropanol (210 mL, 5 M) was addedto the compound 10 (50 g, 0.21 mol) under stirring in an ice-water bath,and the resulting mixture was stirred and reacted for 4 hours undernitrogen. Ethyl acetate (400 mL) was added, and stirred for half anhour. After the filtration, the filter cake was washed with ethylacetate (50 mL), and was put into a flask under nitrogen. The ethylacetate was evaporated under reduced pressure to give 30 g of product,with a yield of 82.2%.

Step 3 Synthesis of Compound 14

Compound 12 (5.0 g, 29.2 mmol) was added to acetonitrile (40 mL) in a100 mL single-necked flask equipped with a magnetic stirrer and acondenser, and stirred to form a solution. 4-Piperidone hydrochloridemonohydrate (compound 13) (5.38 g, 35.1 mmol) and DIPEA (11.3 g, 87.7mol) were sequentially added, and the reaction mixture was heated to 80°C. under nitrogen, at which the mixture was stirred and reactedovernight. After cooling to room temperature, the acetonitrile wasevaporated under reduced pressure. The residue was poured into coldwater (200 mL) under stirring, and a large amount of yellow solid wasprecipitated out, after which, the mixture was stirred for half an hour.After the filtration, the filter cake was washed with water (100 mL),and dried in vacuum. The resulting solid was added to n-hexane (50 mL),heated to reflux for 1 h under stirring, and cooled to room temperature.After the filtration, the residue was dried to give 6.20 g of a yellowsolid, with a yield of 84.8%. LC-MS(APCI): m/z=251.2(M+1)⁺.

Step 4 Synthesis of Compound 15

Compound 14 (1.81 g, 7.2 mmol) and dichloromethane (18 mL) were addedinto a 100 mL single-necked flask equipped with a magnetic stirrer and acondenser, and stirred to form a solution. Compound 11 (1.66 g, 9.4 mol)and DIPEA (2.43 g, 18.8 mol) were sequentially added, and stirred for 10minutes to form a solution. Powder 4 Å molecular sieve (1.44 g) wasadded, and stirred for 10 minutes. Sodium triacetoxyborohydride (3.05 g,14.4 mol) was added in one portion, stirred and reacted overnight underthe protection of nitrogen. Water (40 mL) was added, and stirred for 20minutes. Then the molecular sieve was filtered off through celite, afterwhich the water phase was separated from the filtrate, and thedichloromethane phase was extracted with water (10 mL×3). The waterphases were combined, and ammonia (28%-30%) was added dropwise to adjustthe pH to 10. Dichloromethane (60 mL×3) was added for back extraction.The dichloromethane phases were combined, washed with saturated brine(20 mL), and dried over anhydrous sodium sulfate. After the filtration,the filtrate was concentrated to dryness to give 2.1 g of a yellowsolid, with a yield of 86.5%. LC-MS(APCI): m/z 338.2(M+1)⁺.

Step 5 Synthesis of Compound 16

Compound 15 (1.34 g, 4.0 mmol) and methanol (20 mL) were added into a 50mL single-necked flask equipped with a magnetic stirrer, and stirred toform a solution. Pd/C (0.12 g, 10%) was added, and the resulting mixturewas vacuumed and purged with hydrogen for three times, and stirred andreacted overnight at room temperature under a hydrogen balloon.Dichloromethane (30 mL) was added, and the catalyst was filtered off.The catalyst was washed with dichloromethane (5 mL), and the filtratewas concentrated under reduced pressure to give 1.18 g of a light brownsolid, with a yield of 98.2%. LC-MS(APCI): m/z 308.2(M+1)⁺.

Step 6 Synthesis of Compound 17

Compound 16 (0.62 g, 2.0 mmol) and 1,4-dioxane (10 mL) were added into a50 mL single-necked flask equipped with a magnetic stirrer and acondenser. The resulting mixture was stirred to form a solution, afterwhich compound 6 (0.50 g, 2.28 mmol) and DIPEA(0.8 mL, 5.0 mmol) wereadded. The mixture was heated to 110° C. under nitrogen, stirred andreacted overnight at this temperature. The solvent was evaporated byconcentrating under reduced pressure, and the residue was purified bysilica gel column chromatography to give 0.82 g of a yellow solid, witha yield of 83.7%. LC-MS(APCI): m/z=491.3(M+1)⁺. ¹H NMR(500 MHz, CDCl₃) δ(ppm):10.69(s, 1H), 7.72(s, 1H), 7.35(d, J=2.0 Hz, 1H), 7.13(dd, J=9.5Hz, J=2.0 Hz, 1H), 6.88(d, J=9.5 Hz, 1H), 5.55(s, 1H), 3.89(s, 3H),3.53(d, J=11.5 Hz, 2H), 3.12-2.88(m, 7H), 2.85(q, J=7.0 Hz, 2H), 2.57(t.J=11.5 Hz, 2H), 2.05-1.95(m, 2H), 1.90-1.82(m, 2H), 1.27(t, J=7.0 Hz,3H).

Step 7 Synthesis of Compound T-2

Compound 17 (0.20 g, 0.41 mmol) and DMF (5 mL) were added into a 10 mLmicrowave reaction tube. The resulting mixture was stirred to form asolution, after which compound 8 (0.41 g, 4.1 mmol) and potassiumcarbonate (0.18 g, 1.21 mmol) were added. The mixture was heated to 150°C. in a microwave reactor, and reacted for 2 hours at this temperature.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give 0.16 g of a yellowsolid, with a yield of 70.3%. LC-MS(APCI): m/z=556.3(M+1)⁺. ¹H NMR(300MHz, CDCl₃) δ (ppm):10.69(s, 1H), 7.53-7.46(m, 2H), 6.91(d, J=2.4 Hz,1H), 6.83(d, J=8.8 Hz, 1H), 5.17(br s, 1H), 4.62(d, J=7.2 Hz, 1H),4.29-4.15(m, 1H), 4.14-4.01(m, 2H), 3.87(s, 3H), 3.57-3.51(m, 4H),3.15-2.75(m, 8H), 2.62-2.49(m, 7H), 2.10-1.98(m, 4H), 1.88-1.85(m, 2H),1.62-1.60(m, 2H), 1.34-1.29(m, 3H).

Example 3 Preparation of6-ethyl-3-((3-(methoxy-d₃)-4-(4-(4-(methyl-d₃)piperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-Carboxamide(Compound T-3)

The following route was used for the synthesis:

Step 1 Synthesis of Compound 19

Acetonitrile (20 mL) and compound 2 (1.74 g, 10 mmol) were added into a50 mL single-necked flask equipped with a magnetic stirrer and acondenser. The resulting mixture was stirred to form a solution, afterwhich compound 18 (3.2 g. 12 mmol) and potassium carbonate (2.1 g, 15mmol) were added under stirring. The mixture was heated to 60° C. undernitrogen, stirred and reacted for 2 hours at this temperature. Aftercooling to room temperature, the solvent was evaporated under reducedpressure. Water (60 mL) was added, and a large amount of yellow solidwas precipitated out. After the filtration the residue was washed withwater (20 mL), and dried to give 2.8 g of a yellow solid, with a yieldof 66.2%. LC-MS(APCI): m/z=424.2(M+1)⁺.

Step 2 Synthesis of Compound 20

Compound 19 (2.8 g, 6.6 mmol) and dichloromethane (30 mL) were addedinto a 50 mL single-necked flask equipped with a magnetic stirrer, andstirred to form a solution. Trifluoroacetic acid (10 mL) was addeddropwise under stirring, and the resulting mixture was stirred andreacted for 2 hours at room temperature under nitrogen. The solvent wasevaporated to dryness under reduced pressure, and dichloromethane (30mL) was added. A solution of ammonia in methanol (7M) was added dropwiseunder stiffing, and the pH was adjusted to 10. After stirring for 10minutes, the generated ammonium chloride solid was filtered off, and thefiltrate was concentrated under reduced pressure to give 2.0 g of ayellow solid, with a yield of 93.9%. LC-MS(APCI): m/z=324.2(M+1)⁺.

Step 3 Synthesis of Compound 21

Compound 20 (1.0 g, 3.13 mmol) and MeOD (10 mL) were added into a 50 mLsingle-necked flask equipped with a magnetic stirrer, and stirred toform a solution. A solution of deuterated formaldehyde in heavy water(0.56 g, 3.76 mmol, 20% w/w) and three drops of CH₃COOD were addeddropwise, which was stirred for 10 minutes under nitrogen. Deuteratedsodium cyanoborohydride (0.31 g, 4.70 mmol) was added, and furtherstirred and reacted for 1 hour. Saturated aqueous solution of sodiumbicarbonate (20 mL) was added to quench the reaction, and the resultingmixture was extracted with dichloromethane (30 mL×3). The organic phaseswere combined, washed with saturated brine (20 mL), and dried overanhydrous sodium sulfate. After the filtration and concentration, theresidue was purified by silica gel column chromatography to give 0.85 gof a yellow solid, with a yield of 80.6%. LC-MS(APCI): m/z=341.2(M+1)⁺.

Step 4 Synthesis of Compound 22

Compound 21 (0.68 g, 2.0 mmol) and methanol (10 mL) were added into a 50mL, single-necked flask equipped with a magnetic stirrer and stirred toform a solution. Pd/C (70 mg, 10%) was added, and the resulting mixturewas vacuumed and purged with hydrogen for three times, and stirred andreacted overnight at room temperature under a hydrogen balloon.Dichloromethane (30 mL) was added, and the catalyst was filtered off.The catalyst was washed with dichloromethane (5 mL), and the filtratewas concentrated under reduced pressure to give 0.6 g of a light brownsolid, with a yield of 98.2%. LC-MS(APCI): m/z=311.2(M+1)⁺.

Step 5 Synthesis of Compound 23

Compound 22 (0.6 g, 2.0 mmol) and 1,4-dioxane (10 mL) were added into a50 mL single-necked flask equipped with a magnetic stirrer and acondenser. The resulting mixture was stirred to form a solution, afterwhich compound 6 (0.50 g, 2.28 mmol) and DIPEA (0.8 mL, 5.0 mmol) wereadded. The mixture was heated to 110° C. under nitrogen, stirred andreacted overnight at this temperature. The solvent was evaporated byconcentrating under reduced pressure, and the residue was purified bysilica gel column chromatography to give 0.82 g of a yellow solid, witha yield of 83.7%. LC-MS(APCI): m/z=494.3(M+1)⁺. ¹H NMR(500 MHz, CDCl₃) δ(ppm):10.75(s, 1H), 7.72(s, 1H), 7.35(d, J=2.0 Hz, 1H), 7.13(dd, J=9.5Hz, J=2.0 Hz, 1H), 6.88(d, J=9.5 Hz, 1H), 5.55(s, 1H), 3.53(d, J=11.5Hz, 2H), 2.99-2.75(m, 10H), 2.57(t, J=11.5 Hz, 2H), 2.05-1.95(m, 2H),1.90-1.82(m, 2H), 1.27(t, J=7.0 Hz, 3H).

Step 6 Synthesis of Compound T-3

Compound 23 (0.20 g, 0.41 mmol) and DMF (5 mL) were added into a 10 mLmicrowave reaction tube. The resulting mixture was stirred to form asolution, after which compound 8 (0.41 g, 4.1 mmol) and potassiumcarbonate (0.18 g, 1.21 mmol) were added. The mixture was heated to 150°C. in a microwave reactor, and reacted for 2 hours at this temperature.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give 0.16 g of a yellowsolid, with a yield of 70.3%. LC-MS(APCI): m/z=559.3(M+1)⁺. 1H NMR(400MHz, CDCl₃) δ (ppm):10.69(s, 1H), 7.53-7.46(m, 2H), 6.91(d, J=2.4 Hz,1H), 6.83(d, J=8.8 Hz, 1H), 5.17(br s, 1H), 4.62(d, J=7.2 Hz, 1H),4.29-4.15(m, 1H), 4.14-4.01(m 2H), 3.57-3.51(m, 4H), 3.15-2.75(m, 8H),2.62-2.49(m, 5H), 2.10-1.98(m, 4H), 1.88-1.85(m, 2H), 1.62-1.60(m, 2H),1.34-1.29(m, 3H).

Example 4 Preparation of6-(ethyl-d₅)-3-((3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide(Compound T-4)

The following route was used for the synthesis:

Step 1 Synthesis of Compound 25

Compound 24 (1.72 g, 10 mmol) and DMF (20 mL) were added into a 50 mLsingle-necked flask equipped with a magnetic stirrer, and stirred toform a solution. Compound 8 (1.0 g, 10 mmol) and DIPEA (1.93 g, 15 mmol)were added dropwise in an ice-water bath, after which, the ice-waterbath was removed, and the mixture was stirred and reacted for 2 hours atroom temperature under nitrogen. Water (100 mL) was added to quench thereaction. The resulting mixture was extracted with ethyl acetate (80mL×2), washed with water (100 mL×3), washed with saturated brine (50mL), and dried over anhydrous sodium sulfate. After the filtration andconcentration, the residue was purified by silica gel columnchromatography to give 1.8 g of a yellow solid, with a yield of 75.6%.LC-MS(APCI): m/z=239.2(M+1)⁺. ¹H NMR(500 MHz, CDCl3) δ ppm: 7.78(s, 1H),5.27(br s, 1H), 4.13-4.10(m, 1H), 4.04-4.00(m, 2H), 3.57-3.52(m, 2H),2.05-2.01(m, 2H), 1.63-1.54(m, 2H).

Step 2 Synthesis of Compound 26

Compound 25 (1.5 g, 6.3 mmol) and DMF (10 mL) were added into a 50 mL,single-necked flask equipped with a magnetic stirrer, and stirred toform a solution. NBS (N-bromosuccinimide, 1.57 g, 8.8 mmol) was added.The resulting, mixture was heated to 80° C. under nitrogen, stirred andreacted for 2 hours at this temperature. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography to give 1.7 g of a white solid, with a yield of81.5%. LC-MS(APCI): m/z=317.1(M+1)⁺. ¹H NMR(300 MHz, CDCl3) δ (ppm):5.80(d, J=6.6 Hz, 1H), 4.24-4.16(m, 1H), 4.07-4.02(m, 2H), 3.61-3.52(m,2H), 2.07-2.02(m, 2H), 1.71-1.62(m, 2H).

Step 3 Synthesis of Compound 27

Compound 26 (1.5 g, 4.74 mmol), CuI (8.9 mg, 0.095 mmol) andbis(triphenylphosphine)palladium dichloride (66 mg, 0.095 mmol) wereadded into a 100 mL double-necked flask equipped with a magneticstirrer. The resulting mixture was vacuumed and purged with nitrogen forthree times. Anhydrous THF (30 mL), triethylamine (0.96 g, 9.5 mmol) andtrimethylsilylacetylene (0.55 g, 5.69 mmol) were sequentially addedthrough syringe under nitrogen, after which, the mixture was stirred andreacted for 2 hours at room temperature under nitrogen. Dichloromethane(50 mL) was added, and the insoluble solid was filtered off. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give 1.0 g of a gray solid, with ayield of 80.5%. LC-MS(APCI): m/z=261.1(M−1)⁻. ¹H NMR(300 MHz, CDCl₃) δ(ppm): 5.80(d, J=6.4 Hz, 1H), 4.23-4.20(m, 1H), 4.05-4.01(m, 2H),3.68(s, 1H), 3.60-3.54(m, 2H), 2.06-2.02(m, 2H), 1.67-1.59(m, 2H).

Step 4 Synthesis of Compound 29

Compound 27 (1.0 g, 3.82 mmol) and MeOD (30 mL) were added into a 100 mLsingle-necked flask equipped with a magnetic stirrer, and stirred atroom temperature under nitrogen for 3 hours. Pd/C (100 mg, 10%) wasadded, and the resulting mixture was vacuumed and purged with deuteriumgas for three times, and stirred and reacted at room temperature under adeuterium balloon for 2 hours. Dichloromethane (50 mL) was added, andthe catalyst was filtered off. The catalyst was washed withdichloromethane (5 mL), and the filtrate was concentrated under reducedpressure, and purified by silica gel column chromatography to give 0.8 gof a white solid, with a yield of 79.5%. LC-MS(APCI): m/z=270.2(M−1)⁻.¹H NMR(500 MHz, CDCl₃) δ (ppm): 5.00(d, J=7.0 Hz, 1H), 4.25-4.22(m, 1H),4.05-4.01(m, 2H), 3.60-3.54(m, 2H), 2.06-2.02(m, 2H), 1.60-1.55(m, 2H).

Step 5 Synthesis of Compound 30

Acetonitrile (20 mL) and compound 9 (1.74 g, 10 mmol) were added into a50 mL single-necked flask equipped with a magnetic stirrer and acondenser. The resulting mixture was stirred to form a solution, afterwhich compound 3 (2.2 g, 12 mmol) and potassium carbonate (2.1 g, 15mmol) were added under stirring. The mixture was heated to 60° C. undernitrogen, stirred and reacted for 2 hours at this temperature. Aftercooling to room temperature, the solvent was evaporated under reducedpressure. Water (60 mL) was added, and a large amount of yellow solidwas precipitated out. After the filtration, the residue was washed withwater (20 mL), and dried to give 2.6 g of a yellow solid, with a yieldof 77.1%. LC-MS(APCI): m/z=335.2(M+1)⁺.

Step 6 Synthesis of Compound 31

Compound 30 (1.34 g, 4.0 mmol) and methanol (20 mL) were added into a 50mL single-necked flask equipped with a magnetic stirrer, and stirred toform a solution. Pd/C (0.14 g, 10%) was added, and the resulting mixturewas vacuumed and purged with hydrogen for three times, and stirred andreacted overnight at room temperature under a hydrogen balloon.Dichloromethane (30 mL) was added, and the catalyst was filtered off.The catalyst was washed with dichloromethane (5 mL), and the filtratewas concentrated under reduced pressure to give 1.18 g of a light brownsolid, with a yield of 98.2%. LC-MS(APCI): m/z=305.2(M+1)⁺.

Step 7 Synthesis of Compound 32

Compound 29 (100 mg, 0.37 mmol), compound 31 (347 mg, 1.11 mmol),Pd(OAc)₂ (palladium acetate, 25 mg, 0.11 mmol), BINAP(2,2′-bis(diphenylphosphino)-1,1′-binaphthalene, 69 mg, 0.11 mmol) andcesium carbonate (481 mg, 1.48 mmol) were added into a 50 mLdouble-necked flask equipped with a magnetic stirrer. The resultingmixture was vacuumed and purged with nitrogen for three times, andanhydrous 1,4-dioxane (10 mL) was added through syringe. The resultingmixture was heated to 120° C., stirred and reacted for 4 hours at thistemperature. After cooling to room temperature, dichloromethane (40 mL)was added, and the insoluble solid was filtered off. The filtrate wasconcentrated and purified by silica gel column chromatography to give120 mg of a white powder, with a yield of 60.3%. LC-MS(APCI):m/z=540.4(M+1)⁺. ¹H NMR(400 MHz, CDCl₃) δ (ppm): 7.21(dd, J=8.4 Hz,J=2.0 Hz, 1H), 6.87-6.84(m, 2H), 6.69(s, 1H), 4.75(d, J=7.2 Hz, 1H),4.1-4.08(m, 1H), 4.02-3.99(m, 2H), 3.88(s, 3H), 3.56-3.45(m, 4H),2.90-2.47(m, 11H), 2.41(s, 3H), 2.05-1.95(m, 4H), 1.87-1.79(m, 2H).1.60-1.51(m, 2H).

Step 8 Synthesis of Compound T-4

Compound 32 (120 mg, 0.22 mmol) and MeOD (8 mL) were added into a 50 mLdouble-necked flask equipped with a magnetic stirrer. Then anhydrousDMSO (2 mL) was added under stirring, and stirred to form a solution.Hydrogen peroxide (1 mL, 33%) was slowly added dropwise, after which,the resulting mixture was stirred and reacted at room temperature undernitrogen for half an hour. Acetonitrile (8 mL) was added, and stirredfor 5 minutes. Water (40 mL) and ethyl acetate (40 mL) were added, andthe resulting mixture was allowed to stand for the separation of layers.The organic phase was separated, and the aqueous phase was extractedwith ethyl acetate (40 mL×2). The organic phases were combined, washedwith water (60 mL×2) and saturated brine (30 mL), and dried overanhydrous sodium sulfate. After the filtration and concentration, theresidue was purified by silica gel column chromatography to give 100 mgof a yellow solid, with a yield of 81.6%. LC-MS(APCI): m/z=558.4(M+1)⁺.¹H NMR(500MHz, CDCl₃) δ (ppm): 10.73(s, 1H), 7.51(br s, 1H), 7.46(dd,J=9.0 Hz, J=2.5 Hz, 1H), 6.91(d, J=2.5 Hz, 1H), 6.84(d, J=9.0 Hz, 1H),5.21(br s, 1H), 4.62(d, J=7.0 Hz, 1H), 4.22-4.19(m, 1H), 4.04-4.01(m,2H), 3.87(s, 3H), 3.57-3.51(m, 4H), 2.82-2.48(m, 11H), 2.39(s, 3H),2.10-2.07(m, 2H), 1.96-1.94(m, 2H), 1.87-1.80(m, 2H), 1.61-1.53(m, 2H).

Example 5 Preparation of6-(ethyl-d₅)-3-((3-methoxy-4-(4-(4-(methyl-d₃)piperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide(Compound T-5)

The following route was used for the synthesis:

Step 1 Synthesis of Compound 33

Compound 29 (100 mg, 0.37 mmol), compound 16 (347 mg, 1.11 mmol),Pd(OAc)₂ (25 mg, 0.11 mmol), BINAP (69 mg, 0.11 mmol) and cesiumcarbonate (481 mg, 1.48 mmol) were added into a 50 mL double-neckedflask equipped with a magnetic stirrer. The resulting mixture wasvacuumed and purged with nitrogen for three times, and anhydrous1,4-dioxane (10 mL) was added through syringe. The resulting mixture washeated to 120° C., stirred and reacted for 4 hours at this temperature.After cooling to room temperature, dichloromethane (40 mL) was added,and the insoluble solid was filtered off. The filtrate was concentratedand purified by silica gel column chromatography to give 120 mg of awhite powder, with a yield of 60.3%. LC-MS(APCI): m/z=543.4(M+1)⁺. ¹HNMR(400 MHz, CDCl₃) δ (ppm): 7.21(dd, J=8.4 Hz, J=2.0 Hz, 1H),6.87-6.84(m, 2H), 6.69(s, 1H), 4.75(d, J=7.2 Hz, 1H), 4.1-4.08(m, 1H),4.02-3.99(m, 2H), 3.88(s, 3H), 3.56-3.45(m, 4H), 2.90-2.47(m, 11H),2.05-1.95(m, 4H), 1.87-1.79(m, 2H), 1.60-1.51(m, 2H).

Step 2 Synthesis of Compound T-5

Compound 33 (120 mg. 0.22 mmol) and MeOD (8 mL) were added into a 50 mLdouble-necked flask equipped with a magnetic stirrer. Then anhydrousDMSO (2 mL) was added under stirring, and stirred to form a solution.Hydrogen peroxide (1 mL, 33%) was slowly added dropwise, after which,the resulting mixture was stirred and reacted at room temperature undernitrogen for half an hour. Acetonitrile (8 mL) was added, and stirredfor 5 minutes. Water (40 mL) and ethyl acetate (40 mL) were added, andthe resulting mixture was allowed to stand for the separation of layers.The organic phase was separated, and the aqueous phase was extractedwith ethyl acetate (40 mL×2). The organic phases were combined, washedwith water (60 mL×2) and saturated brine (30 mL), and dried overanhydrous sodium sulfate. After the filtration and concentration, theresidue was purified by silica gel column chromatography to give 100 mgof a yellow solid, with a yield of 81.6%. LC-MS(APCI): m/z=561.4(M+1)⁺.¹H NMR(400MHz, CDCl3) δ (ppm): 10.73(s, 1.H), 7.51(br s, 1.H), 7.46(dd,J=8.8 Hz, J=2.5 Hz, 1H), 6.91(d, J=2.4 Hz, 1H), 6.84(d, J=8.8 Hz, 1H),5.21(br s, 1H), 4.62(d, J=7.2 Hz, 1H), 4.22-4.19(m, 1H), 4.04-4.01(m,2H), 3.87(s, 3H), 3.57-3.51(m, 4H), 2.82-2.48(m, 11H), 2.10-2.07(m, 2H),1.96-1.94(m, 2H), 1.87-1.80(m, 2H), 1.61-1.53(m, 2H).

Example 6 Preparation of6-(ethyl-d₅)-3-((3-(methoxy-d₃)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide(Compound T-6)

The following route was used for the synthesis:

Step 1 Synthesis of Compound 34

Compound 29 (100 mg, 0.37 mmol), compound 5 (347 mg, 1.11 mmol),Pd(OAc)₂ (25 mg, 0.11 mmol). BINAP (69 mg, 0.11 mmol) and cesiumcarbonate (481 mg, 1.48 mmol) were added into a 50 mL double-neckedflask equipped with a magnetic stirrer. The resulting mixture wasvacuumed and purged with nitrogen for three times, and anhydrous1,4-dioxane (10 mL) was added through syringe. The resulting mixture washeated to 120° C., stirred and reacted for 4 hours at this temperature.After cooling to room temperature, dichloromethane (40 mL) was added,and the insoluble solid was filtered off. The filtrate was concentratedand purified by silica gel column chromatography to give 120 mg of awhite powder, with a yield of 60.3%. LC-MS(APCI): m/z=543.4(M+1)⁺. ¹HNMR(400 MHz, CDCl₃) δ (ppm): 7.21(dd, J=8.4 Hz, J=2.0 Hz, 1H),6.87-6.84(m, 2H), 6.69(s, 1H), 4.75(d, J=7.2 Hz, 1H), 4.1-4.08(m, 1H),4.02-3.99(m, 2H), 3.56-3.45(m, 4H), 2.90-2.47(m, 11H), 2.41(s, 3H),2.05-1.95(m, 4H), 1.87-1.79(m, 2H), 1.60-1.51(m, 2H).

Step 8 Synthesis of Compound T-6

Compound 34 (120 mg. 0.22 mmol) and MeOD (8 mL) were added into a 50 mLdouble-necked flask equipped with a magnetic stirrer. Then anhydrousDMSO (2 mL) was added under stirring, and stirred to form a solution.Hydrogen peroxide (1 mL, 33%) was slowly added dropwise, after which,the resulting mixture was stirred and reacted at room temperature undernitrogen for half an hour. Acetonitrile (8 mL) was added, and stirredfor 5 minutes. Water (40 mL) and ethyl acetate (40 mL) were added, andthe resulting mixture was allowed to stand for the separation of layers.The organic phase was separated, and the aqueous phase was extractedwith ethyl acetate (40 mL×2). The organic phases were combined, washedwith water (60 mL×2) and saturated brine (30 mL), and dried overanhydrous sodium sulfate. After the filtration and concentration, theresidue was purified by silica gel column chromatography to give 100 mgof a yellow solid, with a yield of 81.6%. LC-MS(APCI): m/z=561.4(M+1)⁺.¹H NMR(400MHz, CDCl3) δ (ppm): 10.73(s. 1H), 7.51(br s, 1H), 7.46(dd,J=8.8 Hz, J=2.5 Hz, 1H), 6.91(d, J=2.4 Hz, 6.84(d, J=8.8 Hz, 1H),5.21(br s, 1H), 4.62(d, J=7.2 Hz, 1H), 4.22-4.19(m, 1H), 4.04-4.01(m,2H), 3.57-3.51(m, 4H), 2.82-2.48(m, 11H), 2.39(s, 3H), 2.10-2.07(m, 2H),1.96-1.94(m, 2H), 1.87-1.80(m, 2H), 1.61-1.53(m, 2H).

Example 7 Preparation of6-ethyl-3-((3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl-3,3,5,5-d₄)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide(Compound T-7)

The following route was used for the synthesis:

Step 1 Synthesis of Compound 35

Compound 14 (1.0 g, 4 mmol) and deuterated chloroform (80 mL) were addedinto a 250 mL single-necked flask equipped with a magnetic stirrer, andstirred to form a solution. 1,5,7-Triazabicyclo[4.4.0] dec-5-ene (75 mg,0.55 mmol) was added under stirring, and the resulting mixture wasstirred and reacted overnight at room temperature under nitrogen. Themixture was sequentially washed with water (20 mL) and 0.5M hydrochloricacid (10 mL). The organic phase was dried over anhydrous sodium sulfate,filtered and concentrated to dryness to give 0.98 g of a yellow solid,with a yield of 98%. LC-MS(APCI): m/z=255.2(M+1)⁺.

Step 2 Synthesis of Compound 36

Methanol (20 mL) was added into a 100 mL single-necked flask equippedwith a magnetic stirrer, and cooled to 0° C. Compound 35 (0.98 g, 4mmol) was added, and stirred to form a solution. Sodium borohydride (168mg, 4 mmol) was slowly added, and the resulting mixture was stirred andreacted for 5 minutes under nitrogen. Water (5 mL) was added to quenchthe reaction, and stirred at room temperature for 30 min. Water (60 mL)and ethyl acetate (60 mL) were sequentially added, and the organic phasewas separated out. The aqueous phase was extracted with ethyl acetate(30 mL×2) and concentrated. The residue was dissolved in ethyl acetate(50 mL) again, and washed with saturated brine (20 mL×1). The organicphases were dried over anhydrous sodium sulfate, filtered andconcentrated to give 0.99 g of a yellow solid, with a yield of 99%.LC-MS(APCI): m/z=257.2(M+1)⁺.

Step 3 Synthesis of Compound 37

Compound 36 (0.99 g. 4.0 mmol) and dichloromethane (20 mL) were addedinto a 50 mL single-necked flask equipped with a magnetic stirrer, andstirred to form a solution. Triethylamine (0.6 g, 6.0 mmol) was added,and methanesulfonyl chloride (0.57 g, 5.0 mmol) was slowly addeddropwise. The resulting mixture was stirred and reacted at roomtemperature under nitrogen for 1 h. Water (30 mL) was added, shaked andthe organic phase was separated out. The aqueous phase was extractedwith dichloromethane (20 mL×2). The organic phases were combined, andwashed sequentially with 0.5M aqueous solution of hydrochloric acid (20mL×1), saturated aqueous solution of sodium bicarbonate (15 mL×1), andsaturated brine (15 mL×1). The resulting mixture was dried overanhydrous sodium sulfate, filtered and concentrated to give 1.2 g of ayellow solid, with a yield of 89.8%, which was used directly in the nextstep.

Step 4 Synthesis of Compound 38

Compound 37 (1.2 g, 3.6 mmol) and DMF (3 mL) were added into a 50 mLsingle-necked flask equipped with a magnetic stirrer, and stirred toform a solution DIPEA (2.33 g, 18 mmol) and 1-methylpiperazine (3.6 g,36 mmol) were added, and the resulting mixture was heated to 120° C.under nitrogen, and reacted overnight at this temperature. After coolingto room temperature, the solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to give0.6 g of a yellow solid, with a yield of 49.3%. LC-MS(APCI):m/z=339.2(M+1)⁺.

Step 5 Synthesis of Compound 39

Compound 38 (0.6 g, 1.78 mmol) and methanol (10 mL) were added into a 50mL single-necked flask equipped with a magnetic stirrer, and stirred toform a solution. Pd/C (60 mg, 10%) was added, and the resulting mixturewas vacuumed and purged with hydrogen for three times, and stirred andreacted overnight at room temperature under a hydrogen balloon.Dichloromethane (30 mL) was added, and the catalyst was filtered off.The catalyst was washed with dichloromethane (5 mL), and the filtratewas concentrated under reduced pressure to give 0.52 g of a light brownsolid, with a yield of 95.4%. LC-MS(APCI): m/z=309.2(M+1)⁺.

Step 6 Synthesis of Compound 40

Compound 39 (0.52 g, 1.69 mmol) and 1,4-dioxane (10 mL) were added intoa 50 mL single-necked flask equipped with a magnetic stirrer and acondenser. The resulting mixture was stirred to form a solution, afterwhich compound 6 (0.44 g, 2.0 mmol) and DIPEA (0.8 mL, 5.0 mmol) wereadded. The mixture was heated to 110° C. under nitrogen, stirred andreacted overnight at this temperature. The solvent was evaporated byconcentrating under reduced pressure, and the residue was purified bysilica gel column chromatography to give 0.6 g of a yellow solid, with ayield of 72.3%. LC-MS(APCI): m/z=492.3(M+1)⁺.

Step 7 Synthesis of Compound T-7

Compound 40 (0.20 g, 0.41 mmol) and DMF (5 mL) were added into a 10 mLmicrowave reaction tube. The resulting mixture was stirred to form asolution, after which compound 8 (0.41 g, 4.1 mmol) and potassiumcarbonate (0.18 g, 1.21 mmol) were added. The mixture was heated to 150°C. in a microwave reactor, and reacted for 2 hours at this temperature.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give 0.16 g of a yellowsolid, with a yield of 70.3%. LC-MS(APCI): m/z=557.3(M+1⁺. ¹H NMR(400CDCl₃) δ (ppm):10.69(s, 1H), 7.53-7.46(m, 2H), 6.91(d, J=2.4 Hz, 1H),6.83(d, J=8.8 Hz, 1H), 5.17(br s, 1H), 4.62(d, J=7.2 Hz, 1H),4.29-4.15(m, 1H), 4.14-4.01(m, 2H), 3.57-3.51(m, 4H), 3.15-2.75(m, 8H),2.62-2.49(m, 7H), 2.10-1.98(m, 2H), 1.62-1.60(m, 2H), 1.34-1.29(m, 3H).

Example 8 Preparation of6-ethyl-3-((3-methoxy-4-(4-(4-methylpiperazin-1-yl-2,2,3,3,5,5,6,6-d₈)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide(Compound T-8)

The following route was used for the synthesis:

Step 1 Synthesis of Compound 41

Compound 14 (1.81 g, 7.2 mmol) and dichloromethane (18 mL) were addedinto a 50 mL single-necked flask equipped with a magnetic stirrer, andstirred to form a solution. N-Boc-piperazin-2,2,3,3,5,5,6,6-d₈ (1.8 g,9.4 mol) and DIPEA (0.47 g, 3.6 mol) were sequentially added, andstirred for 10 minutes to form a solution. Powder 4 Å molecular sieve(1.44 g) was added, and stirred for 10 minutes. Sodiumtriacetoxyborohydride (3.05 g, 14.4 mol) was added in one portion,stirred and reacted overnight at room temperature under the protectionof nitrogen. Water (40 mL) was added, and stirred for 20 minutes. Thenthe molecular sieve was filtered off through celite, after which thewater phase was separated from the filtrate, and extracted withdichloromethane (30 mL×3). The organic phases were combined, and driedover anhydrous sodium sulfate. After the filtration and concentration,the residue was purified by silica gel column chromatography to give 2.2g of a yellow solid, with a yield of 71.4%. LC-MS(APCI):m/z=429.2(M+1)⁺.

Step 2 Synthesis of Compound 42

Compound 41 (2.2 g, 5.14 mmol) and dichloromethane (20 mL) were addedinto a 50 mL single-necked flask equipped with a magnetic stirrer; andstirred to form a solution. Trifluoroacetic acid (10 mL) was added, andthe resulting mixture was stirred for 2 hours at room temperature undernitrogen. The solvent was evaporated under reduced pressure, anddichloromethane (30 mL) was added. A solution of ammonia in methanol(7M) was added dropwise under stirring, and the pH was adjusted to 10.After stirring for 10 minutes, the generated ammonium chloride solid wasfiltered off, and the filtrate was concentrated under reduced pressureto give 1.6 g of a yellow solid, with a yield of 94.9%, LC-MS(APCI):m/z=329.2(M+1)⁺.

Step 3 Synthesis of Compound 43

Compound 42 (1.0 g, 3.13 mmol) and MeOH (10 mL) were added into a 50 mLsingle-necked flask equipped with a magnetic stirrer, and stirred toform a solution. A solution of formaldehyde in water (0.56 g, 3.76 mmol,20% w/w) and three drops of glacial acetic acid were added dropwise,stirred for 10 minutes under nitrogen. Sodium cyanoborohydride (0.31 g,4.70 mmol) was added, and further stirred and reacted for 1 hour.Saturated aqueous solution of sodium bicarbonate (20 mL) was added toquench the reaction, and the resulting mixture was extracted withdichloromethane (30 mL×3). The organic phases were combined, washed withsaturated brine (20 mL), and dried over anhydrous sodium sulfate. Afterthe filtration and concentration, the residue was purified by silica gelcolumn chromatography to give 0.85 g of a yellow solid, with a yield of80.6%. LC-MS(APCI): m/z=343.2(M+1)⁺.

Step 4 Synthesis of Compound 44

Compound 43 (0.68 g, 2.0 mmol) and methanol (10 mL) were added into a 50mL single-necked flask equipped with a magnetic stirrer, and stirred toform a solution. Pd/C (70 mg, 10%) was added, and the resulting mixturewas vacuumed and purged with hydrogen for three times, and stirred andreacted overnight at room temperature under a hydrogen balloon.Dichloromethane (30 mL) was added, and the catalyst was filtered off.The filtrate was washed with dichloromethane (5 mL), and concentratedunder reduced pressure to give 0.6 g of a light brown solid, with ayield of 98.2%. LC-MS(APCI): m/z=313.2(M+1)⁺.

Step 5 Synthesis of Compound 45

Compound 44 (0.6 g, 2.0 mmol) and 1,4-dioxane (10 mL) were added into a50 mL single-necked flask equipped with a magnetic stirrer and acondenser. The resulting mixture was stirred to form a solution, afterwhich compound 6 (0.50 g, 2.28 mmol) and DIPEA (0.8 mL, 5.0 mmol) wereadded. The mixture was heated to 110° C. under nitrogen, stirred andreacted overnight at this temperature. The solvent was evaporated byconcentrating under reduced pressure, and the residue was purified bysilica gel column chromatography to give 0.82 g of a yellow solid, witha yield of 83.7%. LC-MS(APCI): m/z=496.3(M+1)⁺.

Step 6 Synthesis of Compound T-8

Compound 45 (0.20 g, 0.41 mmol) and DMF (5 mL) were added into a 10microwave reaction tube. The resulting mixture was stirred to form asolution, after which compound 8 (0.41 g, 4.1 mmol) and potassiumcarbonate (0.18 g, 1.21 mmol) were added. The mixture was heated to 150°C. in a microwave reactor, and reacted for 2 hours at this temperature.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give 0.16 g of a yellowsolid, with a yield of 70.3%. LC-MS(APCI): m/z=559.3(M+1)⁺. ¹H NMR(400MHz, CDCl₃) δ (ppm):10.69(s, 1H), 7.53-7.46(m, 2H), 6.91(d, J=2.4 Hz,1H), 6.83(d, J=8.8 Hz, 1H), 5.17(br s, 1H), 4.62(d, J=7.2 Hz, 1H),4.29-4.15(m, 1H), 4.14-4.01(m, 2H), 3.87(s, 3H), 3.57-3.51(m, 4H),2.62-2.49(m, 5H), 2.41(s, 3H), 2.10-1.98(m, 4H), 1.88-1.85(m, 2H),1.62-1.60(m, 2H), 1.34-1.29(m, 3H).

Example 9 Preparation of6-ethyl-3-((3-methoxy-4-(4-(4-(methyl-d₃)piperazin-1-yl-2,2,3,3,5,5,6,6-d₈)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide(Compound T-9)

The following route was used for the synthesis:

Step 1 Synthesis of Compound 46

Compound 42 (1.0 g, 3.13 mmol) and MeOD (10 mL) were added into a 50 mLsingle-necked flask equipped with a magnetic stirrer, and stirred toform a solution. A solution of deuterated formaldehyde in heavy water(0.56 g, 3.76 mmol, 20% w/w) and three drops of CH₃COOD were addeddropwise, stirred for 10 minutes under nitrogen. Deuterated sodiumcyanoborohydride (0.31 g, 4.70 mmol) was added, and further stirred andreacted for 1 hour. Saturated aqueous solution of sodium bicarbonate (20mL) was added to quench the reaction, and the resulting mixture wasextracted with dichloromethane (30 mL×3). The organic phases werecombined, washed with saturated brine (20 mL), and dried over anhydroussodium sulfate. After the filtration and concentration, the residue waspurified by silica gel column chromatography to give 0.85 g of a yellowsolid, with a yield of 80.6%. LC-MS(APCI): m/z=346.2(M+1)⁺.

Step 2 Synthesis of Compound 47

Compound 46 (0.68 g, 2.0 mmol) and methanol (10 mL) were added into a 50mL single-necked flask equipped with a magnetic stirrer, and stirred toform a solution. Pd/C (70 mg, 10%) was added, and the resulting mixturewas vacuumed and purged with hydrogen for three times, and stirred andreacted overnight at room temperature under a hydrogen balloon.Dichloromethane (30 mL) was added, and the catalyst was filtered off.The catalyst was washed with dichloromethane (5 mL), and the filtratewas concentrated under reduced pressure to give 0.6 g of a light brownsolid, with a yield of 98.2%. LC-MS(APCI): m/z=316.2(M+1)⁺.

Step 3 Synthesis of Compound 48

Compound 47 (0.6 g, 2.0 mmol) and 1,4-dioxane (10 mL) were added into a50 mL single-necked flask equipped with a magnetic stirrer and acondenser. The resulting mixture was stirred to form a solution, afterwhich compound 6 (0.50 g, 2.28 mmol) and DIPEA (0.8 mL, 5.0 mmol) wereadded. The mixture was heated to 110° C., under nitrogen, stirred andreacted overnight at this temperature. The solvent was evaporated byconcentrating under reduced pressure, and the residue was purified bysilica gel column chromatography to give 0.82 g of a yellow solid, witha yield of 83.7%. LC-MS(APCI): m/z=499.3(M+1)⁺.

Step 4 Synthesis of Compound T-9

Compound 48 (0.20 g, 0.41 mmol) and DMF (5 mL) were added into a 10 mLmicrowave reaction tube. The resulting mixture was stirred to form asolution, after which compound 8 (0.41 g, 4.1 mmol) and potassiumcarbonate (0.18 g, 1.21 mmol) were added. The mixture was heated to 150°C. in a microwave reactor, and reacted for 2 hours at this temperature.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give 0.16 g of a yellowsolid, with a yield of 70.3%. LC-MS(APCI): m/z=564.3(M+1)⁺. ¹H NMR(400MHz, CDCl₃) δ (ppm):10.69(s, 1H), 7.53-7.46(m, 2H), 6.91(d, J=2.4 Hz,1H), 6.83(d, J=8.8 Hz, 1H), 5.17(br s, 1H), 4.62(d, J=7.2 Hz, 1H),4.29-4.15(m, 1H), 4.14-4.01(m, 2H), 3.87(s, 3H), 3.57-3.51(m, 4H),2.62-2.49(m, 5H), 2.10-1.98(m, 4H), 1.88-1.85(m, 2H), 1.62-1.60(m, 2H),1.34-1.29(m, 3H).

Biological Activity Assay (1) Kinase Activity Evaluation

Reagents and Materials:

Enzyme AXL: Invitrogen-A31516, substrate ULight-poly GT peptide(PerkinElmer-TRF0100-M), antibody Eu-labeled anti-phos (PT66)(PerkinElmer-AD₀₀₆₉), ATP (Sigma, Cat. No. A7699-1G). DMSO (Sigma, Cat.No. D2650), 96-well plate (Corning, Cat. No. 3365), 384-well plate(Greiner, Cat. No. 784076).

Specific Experimental Protocol:

The inhibitory activity of the test compounds against was determined bythe LANCE Ultra TR-FRET method.

The test compounds were dissolved in DMSO, and subjected to a 3-foldserial gradient dilution for 10 times. AXL kinase was transferred withdifferent concentrations of pre-diluted compounds to a 384-well testplate and mixed for 10 minutes, in duplicate. The substrate and ATP wereadded to initiate the reaction, and incubated at room temperature for 90minutes. The final reaction concentrations in the system were: 3 nM AXL,4.75 uM ATP, 50 nM peptide, 50 mM Hepes pH7.5, 1 mM EGTA, 10 mM MgCl₂,0.01% Brij-35, and 2 mM DTT. The maximum concentration of the testcompounds was 300 nM. After the reaction, the detection reagentcontaining 2 mM antibody and 10 mM EDTA was added and incubated at roomtemperature for 60 minutes. Finally, the enzyme activity in the presenceof the compounds of the present disclosure at each concentration wasmeasured by an Evnvision microplate reader, and the inhibition of theenzyme by the compounds at each concentration was calculated. Theinhibitions of the enzyme activity by the compounds at differentconcentrations were then fitted using Graphpad 5.0 software according tothe four-parameter equation, and the IC₅₀ values were calculated.

The compounds of the present disclosure were tested in the above kinaseinhibition assay, which were found to have potent activity against AXLand better inhibitory effect than Gilteritinib. The results for therepresentative example compounds are summarized in Table 1 below:

TABLE 1 AXL Example IC₅₀ compound (nM) Gilteritinib 7.46 T-1 7.35 T-27.01 T-3 6.62 T-4 5.87 T-5 5.33 T-6 5.15 T-7 6.24 T-8 7.10 T-9 6.50

(2) Inhibition of Cell MV-4-11 and Cell MOLM-13

Materials and Instruments:

Cell MV-4-11 (ATCC, Cat. No. CRL-9591), cell MOLM-13 (COBIOER, Cat. No.CBP60678), RPM-1640 (GIBCO, Cat. No. A10491-01), penicillin-streptomycin(GIBCO, Cat. No. 15140-122), fetal bovine serum (GIBCO, Cat. No.10099-141), phosphate buffer solution PBS (GIBCO, Cat. No. 10010-031),DMSO (Sigma, Cat. No. D₈₄₁₈-1L), CelltiterGlo Assay kit (CTG) (Promega.Cat. No. G7573), 96-well plate with transparent flat bottom and blackwalls (PerkinElmer, Cat. No. 6005680-50), plate shaker (QILINBEIER, Cat.No. B-9002), centrifuge (Eppendorf, Cat. No. 5804R), CO₂ incubator(Thermo Scientific, Cat. No. 371), microscope (OLYMPUS Cat. No. CKX41),multi-plate reader (PerkinElmer, Cat. No. EnVision).

Experimental Protocol:

(1) Cell Culture:

The cell culture medium of MV-4-11 was IMDM+10% FBS+1% PS, and the celldensity did not exceed 1×10⁶/ml.

The cell culture medium of MOLM-13 was RPMI1640+20% FBS+1% PS, and thecell density did not exceed 1×10⁶/ml.

(2) Preparation of Cell Suspension

a) The medium was collected from the culture bottle and centrifuged at1000 rpm for 5 min.

b) The supernatant was discarded, and the cells were resuspended inmedium containing 10% fetal bovine serum, and counted to prepare a cellsuspension (cell viability was greater than 90%).

c) The cell suspension was added into a 96-well plate, with 100 μl ineach well, namely 5000 MV-4-11 cells/well; 5000 MOLM-13 cells/well.

d) The cell plate was cultured. overnight in a 37° C., 5% CO₂ incubator.

(3) Preparation of Compounds

Dilution of Compounds in DMSO:

a) MV-4-11 cells: The compounds were diluted with DMSO from 10 mM to 60mM, and then subjected to a 3-fold serial gradient dilution in DMSO from60 uM, resulting in 9 concentrations.

b) MOLM-13 cells: The compounds were diluted with DMSO from 10 mM to 200uM, and then subjected to a 3-fold serial gradient dilution in DMSO from200 uM, resulting in 9 concentrations.

c) Compound Taxol was diluted with DMSO from 10 mM to 200 uM, and thensubjected to a 3-fold serial gradient dilution in DMSO from 200 uM,resulting in 9 concentrations.

(4) Treatment of Cells with Compounds (After the Overnight Incubation ofthe Cell Plate)

a) Each well was replenished with 99 μl of growth medium containing 10%FBS, and then 1 μl of the diluted compound was added to the well. Theconcentration of DMSO was 0.5%.

b) Concentrations of the tested compounds were:

-   -   MV-4-11cells: 300, 100, 33.3, 11.1, 3.7, 1.23, 0.41, 0.137,        0.046, 0 [nM].    -   MOLM-13 cells: 1000, 333.3, 111.1, 37.04, 12.35, 4.1, 1.37,        0.46, 0.15, 0 [nM].

c) Concentrations of control compound Taxol were: 1000, 333.3, 111.1,37.04, 12.35, 4.12, 1.37. 0.46, 0.15, 0 [nM].

d) The cell plate was placed in the incubator for 72 hours.

(5) CTG Assay

a) The test plate was placed at room temperature and equilibrated for 30minutes, and 60 μl of the culture medium was discarded.

b) 60 μl of CTG reagent (CelltiterGlo kit) was added, and the plate wasplaced on a rapid plate shaker to shake for 2min, and then let it standat room temperature for 20 min.

c) Envision was used to read the values.

(6) Data Analysis

IC₅₀ values were calculated using GraphPad Prism 6 software. The IC₅₀(half inhibitory concentration) values of the compounds were obtained bythe following non-linear fitting formula.

Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((LogIC50−X)*HillSlope))

X: Log value of the compound concentration

Y: Inhibition rate (% inhibition)

% inhibition (inhibition rate)=100*(value of the High Control-value ofthe test compound well)/(value of the High Control-value of the LowControl)

The compounds of the present disclosure were tested in the above testexperiments. The results show that, compared with gilteritinib, thecompounds of the present disclosure have more potent activity on cellMV-4-11 and cell MOLM-13. The results of the in vitro proliferationinhibition of cancer cells by representative examples are summarized inTable 2 below.

TABLE 2 MV-4-11 MOLM-1 Example IC₅₀ IC₅₀ compound (nM) (nM) Gilteritinib2.23 14.27 T-1 2.17 15.00 T-2 2.35 14.31 T-3 2.25 14.22 T-4 1.92 12.98T-5 2.01 12.02 T-6 2.07 11.91 T-7 1.64 12.67 T-8 2.17 14.80 T-9 2.0314.52

(3) Inhibition and Selectivity on Ba/F3 FLT3-ITD Cells

Cell lines were cultured under the condition of 37° C., 5% CO₂ and 95%humidity: cell line Ba/F3 parental (suspended, 3000 cells/well, mediumwas RPMI-1640+10% FBS+8 ng/ml IL-3), cell line Ba/F3 FLT3-ITD(suspended, 3000 cells/well, medium was RPMI-1640+10% FBS)

Reagents and materials: Fetal bovine serum (FBS, GBICO, Cat. No.10099-141), CellTiter-Glo® Luminescent Cell Viability Assay (Promega,Cat. No. G7572), 96-well plate with transparent flat bottom and blackwalls (Corning®, Cat. No. 3603), control compound AC220 (Selleck, Cat.No. S1526).

Instruments: SpectraMax multi label microplate reader, MD, 2104-0010A;CO₂ incubator, Thermo Scientific, Model 3100 Series, biosafety cabinet,Thermo Scientific, Model 1300 Series A2, inverted microscope, Olympus,CKX41SF; refrigerator, SIEMENS, KK25E76TI.

Experimental Protocol:

Cell Culture and Inoculation:

1. Cells in the logarithmic growth phase were harvested and countedusing a platelet counter. The cell viability was determined by trypanblue exclusion method to ensure that the cell viability was greater than90%;

2. The cell concentration was adjusted and 90 μL of the cell suspensionwas added into a 96-well plate respectively;

3. The cells in the 96-well plate were cultured overnight under thecondition of 37° C., 5% CO₂ and 95% humidity.

Drug Dilution and Dosing:

1. The 10-fold drug solutions were prepared with a maximum concentrationof 100 μM, which was diluted using a 3.16-fold serialgradient dilution,resulting in 9 concentrations. 10 μL of the drug solutions was added toeach well of the 96-well plate inoculated with Ba/F3 parental cells; andeach drug concentration was set in triplicate.

2. The 10-fold drug solutions were prepared with a maximum concentrationof 10 μM, which was diluted using a 3.16-fold serialgradient dilution,resulting in 9 concentrations. 10 μL of the drug solutions was added toeach well of the 96-well plate inoculated with Ba/F3 FLT3-ITD cells; andeach drug concentration was set in triplicate.

3. The cells in the 96-well plate with drugs were cultured at 37° C., 5%CO₂ and 95% humidity for 72 hours, and then CTG analysis was carriedout.

Plate Reading at the End Point:

1. CTG reagent was thawed and the cell plate was equilibrated to roomtemperature for 30 minutes:

2. Equal volume of the CTG solution was added to each well;

3. The cell plate was shaked on the orbital shaker for 5 minutes to lysethe cells;

4. The cell plate was placed at room temperature for 20 minutes tostabilize the cold light signal;

5. The cold light values were read.

Data Processing

GraphPad Prism 8.0 software was used to analyze the data, and the datawas fitted using the non-linear S-curve regression to get a dose-effectcurve, and IC₅₀ values were calculated.

Cell viability(%)=(Lum of test drug−Lum of medium control)/(Lum of cellcontrol−Lum of medium control)×100%.

The compounds of the present disclosure were tested in the above testexperiments. The results show that, compared with gilteritinib, thecompounds of the present disclosure have more potent activity on Ba/F3FLT3-ITD and superior selectivity over cell Ba/F3 parental. The resultsof the in vitro inhibition of cell proliferation by the representativeexamples are summarized in Table 3 below.

TABLE 3 BaF3 BaF3 parental [FLT3-ITD] Example IC₅₀ IC₅₀ compound (nM)(nM) Selectivity T-1 9715.14 46.45 209 T-2 7160.09 51.30 140 T-3 5368.1189.04 60 T-5 9294.25 94.41 98 T-6 >10000 69.09 145 T-7 8432.19 53.88 156T-8 6870.09 84.99 81 T-9 >10000 72.04 139

(4) Metabolic Stability Evaluation

Microsome assay: human liver microsomes: 0.5 mg/mL, Xenotech; rat livermicrosomes: 0.5 Xenotech, coenzyme (NADPH/NADH): 1 mM, Sigma LifeScience; magnesium chloride: 5 mM, 100 mM phosphate buffer (pH 7.4).

Preparation of stock solutions: Powder of the example compounds and thecontrol compound were accurately weighed and dissolved in DMSO to 5 mMrespectively.

Preparation of phosphate buffer (100mM, pH7.4): A pre-prepared 0.5Mpotassium dihydrogen phosphate (150 mL) was mixed with 0.5M dibasicpotassium phosphate (700 mL). The pH of the mixture was adjusted to 7.4with 0.5M dibasic potassium phosphate solution. The mixture was diluted5-fold with ultrapure water before use, and magnesium chloride was addedto obtain a phosphate buffer (100 mM) containing 100 mM potassiumphosphate, 3.3 mM magnesium chloride, pH 7.4.

A NADPH regeneration system solution (containing 6.5 mM NADP, 16.5 mMG-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride) was prepared andplaced on wet ice prior to use.

Preparation of stop solution: an acetonitrile solution containing 50ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internalstandard), 25057.5 μL of phosphate buffer (pH 7.4) was taken into a 50mL centrifuge tube, to which 812.5 μL of human liver microsomes wereadded, and mixed to obtain a liver microsome dilution with a proteinconcentration of 0.625 mg/mL. 25057.5 μL of phosphate buffer (pH 7.4)was taken into a 50 mL centrifuge tube, to which 812.5 μL of SD ratmicrosomes were added, and mixed to obtain a liver microsome dilutionwith a protein concentration of 0.625 mg/mL.

Incubation of the samples: The stock solutions of the respectivecompounds were respectively diluted to 0.25 mM with an aqueous solutioncontaining 70% acetonitrile, and used as a working solution, ready foruse. 398 μL of the dilutions of human liver microsomes and rat livermicrosomes were added to 96-well incubation plates (N=2), respectively,and 2 μL of 0.25 mM working solution was added respectively and mixed.

Metabolic stability assay: 300 μL of pre-chilled stop solution was addedto each well of 96-well deep well plates and placed on ice as stopplates. The 96-well incubation plates and NADPH regeneration system wereplaced in a 37° C. water bath, shaken at 100 rpm and pre-incubated for 5min. 80 μL of incubation solution was taken out from each well of theincubation plates and added to the stop plates, mixed, and replenishedwith 20μL of NADPH regeneration system solution as a 0-min sample. 80 μLof NADPH regeneration system solution was added to each well of theincubation plates to start the reaction and start counting. Thecorresponding compounds had a reaction concentration of 1 μM and theprotein concentration was 0.5 mg/mL. Separately, 100 μL of the reactionsolutions was taken at 10, 30, and 90 min after the reaction,respectively, added to stop plates, and vortexed for 3 minutes toterminate the reaction. The stop plates were centrifuged at 5000×g at 4°C. for 10 min. 100 μL of the supernatant was added to a 96-well plate towhich 100 μL of distilled water was previously added, mixed, andanalyzed by LC-MS/MS.

Data analysis: The peak areas of the corresponding compounds andinternal standard were detected by LC-MS/MS system, and the ratio of thepeak area of the compounds to the internal standard was calculated. Theslope was measured by plotting the natural logarithm of the percent ofremaining compound versus time, and t_(1/2) and CL_(int) were calculatedaccording to the equation below, where V/M equals to 1/proteinconcentration.

${t_{1/2} = {- \frac{{0.6}93}{slope}}},{{CL}_{int} = {\frac{{0.6}93}{t_{1/2}} \cdot \frac{V}{M}}},{{t_{1/2}\left( \min \right)};{{{CL}_{int}\left( {{µL}\text{/}\min \text{/}{mg}} \right)}.}}$

The metabolic stability of the compounds in human and rat livermicrosomes was evaluated by simultaneously testing and comparing thecompounds disclosed herein and the non-deuterated compound. Thenon-deuterated compound Gilteritinib was used as a control sample. Inthe human and rat liver microsome assays, compared with thenon-deuterated compound Gilteritinib, the compounds of the presentdisclosure can significantly improve the metabolic stability.

TABLE 4 Human liver microsome assay Compound t_(1/2) CL_(int) No. (min)(μL/min/mg) Gilteritinib 164.9 8.4 T-2 217.6 6.4 T-3 199.8 6.9 T-5 188.37.4 T-8 261.7 5.3 T-9 472.6 2.9

(5) Pharmacokinetic Experiment in Rats

Six male Sprague-Dawley rats, 7 to 8 weeks old, weighing approximately210 g, were divided into 2 groups with 3 rats in each group. Thepharmacokinetic differences of the compounds were compared after theywere administered to the rats at a single dose through vein (in vein 10mg/kg) or mouth (orally 10 mg/kg).

The rats were fed with standard feed and water, and fasted 16 hoursbefore the experiment. The drugs were dissolved with PEG400 and dimethylsulfoxide. The blood samples were collected from eyelids at the timepoint of 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours afteradministration.

The rats were anesthetized for a short time after inhaling ether, and300 μL of blood samples was collected from the eyelids and put into testtubes, which contains 30 μL of 1% heparin salt solution. The test tubeswere dried overnight at 60° C. prior to use. After the blood samplecollection at the last time point, the rats were sacrificed after theether anesthesia.

Immediately after the collection of the blood samples, the test tubeswere gently inverted at least 5 times to ensure the fully mixing andplaced on ice. The blood samples were centrifuged at 4° C., 5000 rpm for5 minutes to separate the plasma from the red blood cells. 100 μL ofplasma was pipetted into a clean plastic centrifuge tube, with the nameof the compound and time point on it. The plasma was stored at −80° C.before analysis, and LC-MS/MS was used to determine the concentration ofthe compounds disclosed herein in plasma. Pharmacokinetic parameterswere calculated based on the plasma concentrations of each animal atdifferent time points.

The experiment shows that the compounds disclosed herein have betterpharmacokinetic properties in animals, and therefore have betterpharmacodynamics and treatment effects. The results of thepharmacokinetic experiment in rats for the representative examplecompounds are summarized in Table 5 below.

TABLE 5 Gilteritinib T-1 T-4 PK IV PO IV PO IV PO Dose 3 mg/kg 10 mg/kg3 mg/kg 10 mg/kg 3 mg/kg 10 mg/kg T_(max) (h) 0.08 8.00 0.08 5.33 0.084.00 C_(max) (ng/mL) 196.2 34.6 138.1 48.4 137.5 61.2 AUC_(last) (h *ng/mL) 449.4 316.9 555.9 510.0 638.8 665.5 AUC_(INF)_pred (h * ng/mL)508.7 435.2 572.0 578.2 651.3 686.6 MRT_(INF)_pred (h) 3.44 7.46 4.207.89 4.56 8.11 Vz_pred (L/kg) 34.89 212.0 28.80 162.8 30.45 87.60Cl_pred (L/kg) 5.92 25.50 5.56 19.03 4.67 14.91 T_(1/2) (h) 4.08 5.763.59 5.93 4.52 4.07 F(%) 21.15 27.52 31.26

The above content is a further detailed description disclosed herein incombination with specific preferred embodiments, and it cannot beassumed that the specific implementation disclosed herein is limited tothese descriptions. For a person of ordinary skill in the art to whichthe present disclosure pertains, a number of simple deductions orsubstitutions can be made without departing from the concept disclosedherein, and should all be considered as falling within the protectionscope disclosed herein.

1. A compound of formula (Φ), or a pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof:

wherein, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³ and R²⁴ are independentlyselected from hydrogen or deuterium; X¹ and X² are independentlyselected from CH₃, CD₃, CHD₂ or CH₂D; X³ is selected from CH₂CH₃,CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃, CD₂CH₃,CD₂CH₂D, CD₂CHD₂ or CD₂CD₃; Y¹, Y² and Y³ are independently selectedfrom hydrogen or deuterium; with the proviso that the compound containsat least one deuterium atom.
 2. The compound, or the pharmaceuticallyacceptable salt, prodrug, hydrate, solvate, polymorph, stereoisomer orisotopic variant thereof according to claim 1, which is a compound offormula (I):

wherein, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³ and R²⁴ are independentlyselected from hydrogen or deuterium; X¹ and X² are independentlyselected from CH₃, CD₃, CHD₂ or CH₂D; X³ is selected from CH₂CH₃,CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃, CD₂CH₃,CD₂CH₂D, CD₂CHD₂ or CD₂CD₃; with the proviso that the compound containsat least one deuterium atom.
 3. The compound, or the pharmaceuticallyacceptable salt, prodrug, hydrate, solvate, polymorph, stereoisomer orisotopic variant thereof according to claim 1, which is a compound offormula (II):

wherein, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹², areindependently selected from hydrogen or deuterium; X¹ and X² areindependently selected from CH₃, CD₃, CHD₂ or CH₂D; X³ is selected fromCH₂CH₃, CH₂CH₂D, CH₂CHD₂, CH₂CD₃, CHDCH₃, CHDCH₂D, CHDCHD₂, CHDCD₃,CD₂CH₃, CD₂CH₂D, CD₂CHD₂ or CD₂CD₃; with the proviso that the compoundcontains at least one deuterium atom.
 4. The compound according to claim1, wherein R⁹, R¹⁰, R¹¹ and R¹² are hydrogen.
 5. The compound accordingto claim 1, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are hydrogen. 6.The compound according to claim 1, wherein X² is CD₃.
 7. The compoundaccording to claim 1, wherein X¹ is CD₃.
 8. The compound according toclaim 1, wherein X³ is CD₂CD₃.
 9. The compound, or the pharmaceuticallyacceptable salt, prodrug, hydrate, solvate, polymorph, stereoisomer orisotopic variant thereof according to claim 1, wherein the compound isselected from any one of the following compounds:


10. A pharmaceutical composition, comprising pharmaceutically acceptableexcipient(s) and the compound, or the pharmaceutically acceptable salt,prodrug, hydrate, solvate, polymorph, stereoisomer or isotopic variantthereof according to claim
 1. 11. A method of treating FLT3kinase-mediated diseases in a subject, comprising administering aneffective amount of the compound, or the pharmaceutically acceptablesalt, prodrug, hydrate, solvate, polymorph, stereoisomer or isotopicvariant thereof according to claim
 1. 12. (canceled)
 13. A method oftreating AXL kinase-mediated diseases in a subject, comprisingadministering an effective amount of the compound, or thepharmaceutically acceptable salt, prodrug, hydrate, solvate, polymorph,stereoisomer or isotopic variant thereof according to claim
 1. 14.(canceled)
 15. A method of treating acute myeloid leukemia in a subject,comprising administering an effective amount of the compound, or thepharmaceutically acceptable salt, prodrug, hydrate, solvate, polymorph,stereoisomer or isotopic variant thereof according to claim
 1. 16. Amethod of treating FLT3 kinase-mediated diseases in a subject,comprising administering the pharmaceutical composition according toclaim
 10. 17. A method of treating AXL kinase-mediated diseases in asubject, comprising administering the pharmaceutical compositionaccording to claim 10.